DEPARTMENT OF

MOLECULAR GENETICS,

MICROBIOLOGY

& IMMUNOLOGY

ANNUAL REPORT

JULY 1, 2004 - JUNE 30, 2005

SIDNEY PESTKA, M.D.

PROFESSOR AND CHAIRMAN

Table of Contents

Preface ............................................................................................................................................ 1

Introduction .................................................................................................................................... 2

Research Activities ........................................................................................................................ 5

Personnel........................................................................................................................................ 9

Departmental Activities ............................................................................................................... 13

Departmental Committees .......................................................................................................... 15

Activities of the Faculty Members.............................................................................................. 16

Gary Brewer, Ph.D. .................................................................................................... 17

Paul R. Copeland, Ph.D. ............................................................................................ 20

Joseph P. Dougherty, Ph.D........................................................................................ 24

Donald T. Dubin, M.D. ................................................................................................ 28

Terri Goss Kinzy, Ph.D. .............................................................................................. 29

Jerome Langer, Ph.D. ................................................................................................ 35

Michael J. Leibowitz, M.D., Ph.D................................................................................ 38

Honghua Li, Ph.D. ...................................................................................................... 45

Michael Newlon, Ph.D. ............................................................................................... 49

Stuart W. Peltz, Ph.D.................................................................................................. 50

Sidney Pestka, M.D., Chairman ................................................................................. 51

Arnold B. Rabson, M.D............................................................................................... 59

Yacov Ron, Ph.D. ....................................................................................................... 64

Aaron J. Shatkin, Ph.D. .............................................................................................. 66

Yufang Shi, D.V.M., Ph.D. .......................................................................................... 70

Victor Stollar, M.D., Vice Chairman............................................................................ 76

Nancy Woychik, Ph.D................................................................................................. 79

Research Activities of Joint and Adjunct Faculty .................................................................... 82

Sefik S. Alkan, Ph.D. .................................................................................................. 83

David Beck, Ph.D. ...................................................................................................... 84

Bruce Byrne, Ph.D...................................................................................................... 85

C. Thomas Caskey, M.D. ........................................................................................... 86

Graham Cleaves, Ph.D............................................................................................... 87

Dalia Cohen, Ph.D...................................................................................................... 87

Jeffry R. Cook, Ph.D................................................................................................... 91

Lori R. Covey, Ph.D.................................................................................................... 93

Jonathan Dinman, Ph.D. ............................................................................................ 94

Ellen C. Ebert, M.D..................................................................................................... 97

Evelyn S. Erenrich ...................................................................................................... 98

Arthur M. Felix, Ph.D. ............................................................................................... 100

Janusz J. Godyn, M.D. ............................................................................................. 101

Alice B. Gottlieb, M.D., Ph.D. ................................................................................... 105

Suhayl Dhib-Jalbut, M.D........................................................................................... 106

Christopher G. Janson, M.D..................................................................................... 108

Edmund C. Lattime, Ph.D......................................................................................... 109

Paola Leone, Ph.D. .................................................................................................. 111

Mei-Ling Li, Ph.D. ..................................................................................................... 113

Randall D. McKinnon, Ph.D...................................................................................... 113

M. Maral Mouradian, M.D. ........................................................................................ 115

Margaret Prescott, Ph.D. .......................................................................................... 118

Karel Raska, M.D. .................................................................................................... 119

Michael Reiss, M.D................................................................................................... 120

Hugh Rosen, Ph.D.................................................................................................... 122

Srijata Sarkar, Ph.D.................................................................................................. 124

Lee Ann Schein, Ph.D. ............................................................................................. 125

Leonard H. Sigal, M.D. ............................................................................................. 128

Roger Strair, M.D., Ph.D........................................................................................... 129

Michael Steinmetz, Ph.D. ......................................................................................... 132

George B. Weiss, Ph.D. ........................................................................................... 132

Lawrence P. Wennogle, Ph.D. ................................................................................. 132

Carol Wilusz, Ph.D. .................................................................................................. 132

Jinxia Xie, Ph.D. ....................................................................................................... 133

Core Facilities............................................................................................................................. 136

Doctoral Program....................................................................................................................... 139

Courses .................................................................................................................................. 142

Microbiology for Physician Assistants ...................................................................... 142

Medical Genetics ...................................................................................................... 149

Medical Microbiology and Immunology .................................................................... 154

Holowczak Memorial Fund........................................................................................................ 159

Research Grant Support ........................................................................................................... 160

Gary Brewer ............................................................................................................. 160

Paul R. Copeland, Ph.D. .......................................................................................... 161

Joseph P. Dougherty, Ph.D...................................................................................... 162

Terri Goss Kinzy, Ph.D. ............................................................................................ 163

Jerome Langer, Ph.D. .............................................................................................. 165

Michael J. Leibowitz, M.D., Ph.D.............................................................................. 166

Honghua Li, Ph.D. .................................................................................................... 168

Sidney Pestka, M.D., Chairman ............................................................................... 169

Arnold B. Rabson, M.D............................................................................................. 171

Yacov Ron, Ph.D. ..................................................................................................... 172

Yufang Shi, D.V.M., Ph.D. ........................................................................................ 173

Victor Stollar, M.D., Vice Chairman.......................................................................... 174

Nancy Woychik, Ph.D............................................................................................... 175

Summary of Outside Grant Support ......................................................................... 176

Seminars .................................................................................................................................. 177

Departmental Retreat................................................................................................................. 178

Departmental Organization Chart............................................................................................. 180

PREFACE

Members of the department faculty continue to perform impressively. Many have been involved in organizing high profile symposia; they are routinely invited to lecture at national and international meetings, and to serve on national committees. The department has continued its initiative to develop core facilities for the medical school and to maintain them at departmental expense. The DNA Synthesis and Sequencing Facility and the imaging facility have been functional for many years. The services of these facilities have been continually upgraded to provide both RWJMS-UMDNJ and Rutgers investigators with the resources they need to be competitive. Equipment to carry out analysis of fluorescence resonance energy transfer in single cells in real time was constructed so that members of the faculty and other investigators could identify specific protein-protein interactions in cells. The department faculty has been successful in obtaining new grants; the number of grants for the year totaled thirty nine. Through the efforts of Drs. Michael Leibowitz, Jerome Langer and Evelyn Erenrich, two major grants from the National Institutes of Health continue to support one of the largest programs in the nation for recruitment of under-represented populations into the biomedical sciences. The faculty have been productive not only in their research and publications, but also in teaching, service to the medical school, university and community, and in mentoring. The mentoring program of the department established over a decade ago has contributed to the success of new investigators in obtaining grants and in developing their teaching skills. The extensive work of faculty members on school, university and community activities has provided a model for the younger faculty to follow. These and many other items are discussed further in this annual report.

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INTRODUCTION

The members of the Department continue to be in the forefront of research in many areas in microbiology, immunology, biochemistry, virology, yeast, mammalian and E. coli molecular biology and in receptors and signal transduction. Translation, transcription, signal transduction, retroviruses, receptors, mechanism of tumor development, regulation of gene expression, and mRNA turnover are major areas of interest.

The full time tenured or tenure track faculty consists of 7 full professors, 3 associate professors and 2 assistant professors. The non-tenure track research faculty consists of 5 assistant professors.

This past year Gorbdhan Das, Ph.D. joined the Department as a volunteer adjunct assistant professor. Dr. Das received his Ph.D. in Immunology from Panjab University, Chandigarh India in 1997. He is currently a principal scientist at Aventis-Sanofil. We look forward to his participation in lecturing in the medical student course in Microbiology and Immunology and in the graduate course in Immunology. We also welcome Janice Berliner as an Adjunct Instructor. Adjunct assistant professors, Jeffry Cook, Ph.D. and Junxia Xie, Ph.D., left our staff and will retain volunteer adjunct assistant professor positions in the department.

The office staff of the Department continues to carry out their many duties. Walter Barnes, Budget Analyst Ill, is responsible for maintaining, reviewing, and analyzing the departmental accounts. Ellen Feibel, Senior Management Assistant, under the supervision of the department chairman, performs a wide variety of administrative and secretarial services. Nancy Stevens, Secretary I, performed secretarial services and assisted with the administrative activities of the department until she left the department in February of 2005. Rosalie Reina, Program Assistant, serves as the primary contact for undergraduate trainees involved in the UMDNJ-Rutgers University Pipeline program and in coordinating the efforts necessary for the training grant “Virus-Host Interactions in Eukaryotic Cells”. Charnel Bohn, Administrative Analyst, was responsible for grant administration until she left the department in May 2005. Toni Thomas, Secretary IV, assists departmental staff with various administrative and secretarial services. Rick Wernoski, MPA, Business Manger, is responsible for all day-to-day operations of the department including financial, administrative, staffing and facility needs. In the Department core facilities, Zofia Andes, Principal Laboratory Assistant, and May Tang, Laboratory Service Worker, are

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responsible for washing and sterilizing glassware. Octavia Gamble, Research Teaching Specialist, prepares bacterial and agar plates as well as sterile tissue culture media and solutions for the department. In February 2005 Andrea Finamore, Administrative Coordinator II, who performs the human resources administrative functions for the department as well as other administrative activities joined the office staff. Jamie Carr, Administrative Analyst, joined the office staff in June 2005 and is responsible for grant administration.

Dr. Michael Leibowitz, in collaboration with Drs. Jerome Langer and Evelyn Erenrich, serves as Program Director of three grants supporting the training of underrepresented minority students in the sciences on the Piscataway/New Brunswick campuses of UMDNJ and Rutgers University. Now in its second 4-year funding period, an Initiative for Minority Student Development Award from the NIH provides about $500,000 per year that supports the UMDNJ-Rutgers University Pipeline Program. This program supports Ph.D. and M.D./Ph.D. candidates as well as supervised individual research experiences for undergraduate and medical students. Undergraduate programs include the summer Research in Science and Engineering (RISE) Program at Rutgers/UMDNJ. This program is a major outreach program, many of whose alumni have gone on to succeed in graduate studies here and elsewhere. In addition to the Pipeline Program, the NIH-funded Bridge to the Doctoral Degree Program supports an articulated M.S./Ph.D. Program run jointly with the University of Puerto Rico, Mayaguez Campus, is in its second funding period. An additional Bridge Program proposal, run jointly with Montclair State University, has been awarded.

Dr. Michael Newlon continues to direct the Microbiology/Immunology and Medical Genetics courses for first-year medical students and the Microbiology/Immunology course for students in the physician assistant program. The department continued to increase web-based instruction in these courses, and has added visual resources and interactive quizzes.

Dr. Victor Stollar, as Vice Chairman of the department, assists the department chairman in many ways and is always available for advice and consultation on all matters which bear on the functioning of the department. Such matters pertain not only to the internal functioning of the department, but also to the role of the department in the medical school. Dr. Stollar is often substitutes for the chairman at various functions, particularly when the chair has scheduling conflicts.

Members of the Department continued to compete well for research grants despite the difficult funding environment. Total funding for this academic year was over $7,500,000; and the total number of grants 47. The faculty continues to

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be highly productive with a total of 50 publications in peer-reviewed journals. In addition, members of the faculty have published reviews in several prestigious journals.

The members of the Department continue to distinguish themselves in teaching, research and service. They have made significant achievements in each of these areas.

The annual department retreat was held on August 26, 2004, at the Hilton Garden Inn in Bridgewater, New Jersey. The goal of the retreats is to give students and postdoctoral fellows an opportunity to present their work in a formal setting. In addition, the retreat provides an opportunity for the building of relationships and camaraderie within the department. Each laboratory presented a 12 minute presentation, which was followed by a question and answer period. The program of the retreat is provided later in this report. A buffet style lunch followed the presentations.

The DNA Synthesis and Sequencing Core Facility of the Department of Molecular Genetics, Microbiology and Immunology serves as a shared resource for faculty of Robert Wood Johnson Medical School and Rutgers. In addition this facility provides core resources for two joint institutes of RWJMS and Rutgers, the Cancer Institute of New Jersey (CINJ) and The National Institute of Environmental Health Sciences (NIEHS) Center at the Environmental and Occupational Health Sciences Institute (EOHSI). The overall purpose of this shared resource is to provide a centralized, high quality, cost-effective facility for DNA synthesis and sequencing for use by the entire scientific community at UMDNJ-RWJMS and Rutgers University. By providing synthetic oligonucleotides to all members of the University, many studies are greatly facilitated at significant cost discounts over what individual laboratories could obtain. Terri Goss Kinzy, Ph.D., Professor of Molecular Genetics, Microbiology and Immunology is Executive Director of this facility and Lee Ann Schein, Ph.D., is Director. This is one example where departmental resources have been used to develop a core facility that is essential for the scientific development of RWJMS. Mr. Rick Wernoski is the Business Manager of this facility.

DNA Microarray Facilities were initiated from a shared instrumentation grant received by Dr. Pestka. A portion of the funds were used to establish the facilities at the CINJ in New Brunswick and in Piscataway to make it most accessible to investigators in both locations. The facility in Piscataway includes a Phosphorimager for analysis of the DNA microarrays. This is a shared facility open to investigators of RWJMS, Rutgers and all members of the UMDNJ community. We have also opened it up to outside academic and commercial

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institutions to facilitate collaborations and general research programs in New Jersey. This facility is used extensively. With the departure of Dr. Jeffry Cook, Dr. Gary Brewer is now the Director of the facility. This is a second example where departmental resources are used to support the scientific development of RWJMS, Rutgers and UMDNJ. Mr. Rick Wernoski is also the Business Manager of this facility.

In summary, the Department has continued to contribute to many areas in strengthening the school in research, teaching, and training of scientists and physicians, all of which are important objectives of the University. As described under the individual summaries, the members have also contributed to community service in many ways. Research Activities

The research activities in the department continue to open up new areas. Some highlights are given below; details are provided in a later section.

Dr. Brewer published two seminal papers reporting the yin/yang regulation of cellular proliferation by IMP1 and IMP3. These papers address the mechanisms as to how the antagonistic actions of these two RNA-binding proteins control proliferation.

Dr. Copeland this year has published his laboratory’s findings that SBP2

functions as a monomer, thus complicating its dual role as a SECIS binding protein and a ribosome binding protein. Interestingly, a wild-type but not a mutant SECIS element is able to effectively compete with the SBP2 ribosome interaction, indicating that SBP2 cannot simultaneously interact with the ribosome and the SECIS element. These data also support the hypothesis that SBP2 interacts with one or more kink turns on 28S rRNA. Based on these results we propose a revised model for selenocysteine incorporation where SBP2 remains ribosome bound except during selenocysteine delivery to the ribosomal A-site.

Dr. Dougherty developed a model of viral latency that can be used for anti-HIV

drug discovery aimed at purging virus infection. He and his laboratory staff discovered that the recombination rate of disparate retroviruses is very high suggesting that all retroviruses including HIV are always subject to recombination crossovers during each and every cycle of replication. They also discovered that the translation termination factor eRF3 interacts with RNase L, which is important in mediating interferon activity, suggesting that RNase L plays a role in regulating gene expression by modulating the translation termination process.

In Dr. Kinzy’s Laboratory the understanding of the role of the translation

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elongation factors has extended beyond their canonical role in protein synthesis. Several of the subunits have been linked, through their work and that of their collaborators, to cellular processes such as proteosome-dependent protein degradation and the regulation of the actin cytoskeleton. Additionally, the regulatory role of the guanine nucleotide exchange factor complex is now linked to the specific post-transcriptional regulation that occurs in response to oxidative stress.

Dr. Langer has received funding from the Alliance for Lupus Research for the

design of inhibitors of Type I interferon that might be useful in the treatment of lupus (systemic lupus erythematosus). He is designing mutants of human interferon alpha that are hoped to be competitive antagonists of natural interferon; i.e., they will bind to the receptor, but will not trigger biological responses, and will block the activity of endogenous interferon. The project is a collaboration with Dr. Elizabeth Raveche (Dept. of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School). He also had several training grants renewed through the MORE division of NIGMS for graduate student support, including an “Initiative to Maximize Student Diversity” (IMSD) grant (Michael J. Leibowitz, PI; JA Langer, Co-PI and Program Director), and the AMSU-UMDNJ-GSBS Bridge to the Doctorate@ NIH/NIGMS R25 ABridge to the Doctorate@,

Dr. Leibowitz studies [KIL-d], a cytoplasmically-inherited element in yeast

which epigenetically regulates expression of the M double-stranded (ds) RNA genomic segment of the cytoplasmic killer virus. He has previously shown that [KIL-d] does not localize on the M or L-A viral dsRNA segments, mitochondrial DNA or 2-micron DNA. Although [KIL-d] has many properties of prions of yeast, until now its molecular nature has not been elucidated. He has recently shown that [KIL-d] can be transmitted from strain to strain by a protein extract, using a method that also transmits other yeast prions; this method fails to transmit killer virus. Studies are underway to identify the molecular nature of the transmissible principle carrying [KIL-d], with the goal of identifying the protein and the gene encoding it. Since the epigenetic effect of [KIL-d] regulates expression of the RNA viral genome but not of a cDNA derived from it, this may represent an exciting model system for studying the interactions of prions and viruses in eukaryotic cells.

Dr. Li has made significant progress toward extending the application of his

high-throughput nucleic acid detection system. This system has been used for studying the details of meiotic recombination. He has also used it for studying genetic variation in breast cancer tissues and cell lines, and in colon cancer. He has been very successful in using this marker system, for the first time, to detect meiotic recombination along entire chromosomes and to locate meiotic crossover points, thus improving the understanding of the mechanisms underlying meiotic recombination. He has also made significant progress in understanding the genetic structure of the human immunoglobulin VH region. This information may have significant impact on understanding the contribution of genetic structure of the VH region to the function of the immune system

Dr. Peltz has been on a leave of absence beginning November 2004 and

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continuing through December 2005. The work of his lab is now under the supervision of Dr. Joseph Dougherty.

Dr. Pestka in this year discovered that the spliceosome Sm proteins D1, D3,

and B/B' are asymmetrically dimethylated at arginine residues in the nucleus. He also discovered that the IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix and is dependent on N-linked glycosylation. Dr. Pestka and his laboratory designed and constructed a phosphorylatable chimeric monoclonal antibody with a highly stable phosphate. They also discovered PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine as well as new Class 2 cytokines and receptors in many vertebrates and in humans, including new interferons. In September 2004, Dr. Pestka was honored with the Warren Alpert Prize at Harvard.

Dr. Rabson’s laboratory has delineated a pathway for activation of latent HTLV-

1 through T-cell receptor activation. This result provides a possible mechanism for the pathogenesis of HTLV-1-induced diseases, in particular, Adult T-cell leukemia (ATL). Dr. Rabson hypothesizes that T-cell activation may lead to induction of latent HTLV-1 leading to expression of the viral oncogene, Tax. Induction of Tax expression would then lead to T-cell proliferation ultimately contributing to the oligoclonal and monoclonal proliferation associated with progression of HTLV-1 leukemia. Dr. Rabson’s collaborations with Drs. Stein, Leibowitz, Sinko and Pilch suggest new therapeutic targets and drug delivery approaches for HIV infection.

Dr. Ron has used retroviral tagging to identify a myeloid precursor cell

population in mouse spleen that can give rise to the whole myeloid system. This population is long-lived and will reconstitute the myeloid system for at least six months.

Dr. Shatkin demonstrated that mRNA modification is essential in

mammalian cells and that disruption of any one of the three enzymatic activities responsible for mRNA 5’ capping induces programmed cell death.

Dr. Shi, in the past year, has made significant progress in several areas. He

has made significant advances in our understanding of the role of granzyme B in the regulation of Th2 apoptosis. Mice deficient in granzyme B develop more severe allergic asthma. He also made significant progress in the understanding of the mechanisms that regulate RANKL expression in T cells. His new in vivo system provided him with a unique opportunity to study how apoptotic cells regulate immune response. The establishment of the mesenchymal stem cell project gives him a unique niche to use his immunology expertise to investigate the mechanisms controlling mesenchymal stem cell-mediated immunosuppression. This study may provide new information for proper clinical use of these cells. His project on stress and radiation has been focused on the development of new countermeasures in response to the directional changes in NASA research. He has shown that vitamin C can effectively protect mice thymocytes from stress induced reduction. He also found that CD4+CD25+ T regulatory cells play a key role in stress- induced peripheral lymphocyte reduction.

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Dr. Stollar continues to work with the development of a system for assaying the binding of the Sindbis-virus transcriptase to the SG promoter. Experiments with this system showed that the viral RDRP (nsP4), by itself did not bind to the promoter; for binding to occur all four of the nonstructural proteins had to be present. Additionally, an amino acid sequence was identified in nsP4 that was directly involved in the binding to the SG promoter. The development of this system and the findings just described represent significant new developments in the alphavirus field.

Dr. Woychik, this year, continued her transition to new avenues of research

with the addition of five new students, three Ph.D. and two M.S. students, to the laboratory.

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PERSONNEL Faculty Gary Brewer, Ph.D., Professor Paul Copeland, Ph.D., Assistant Professor Joseph P. Dougherty, Ph.D., Professor Donald T. Dubin, M.D., Professor Terri Goss Kinzy, Ph.D., Professor Jerome A. Langer, Ph.D., Associate Professor Michael J. Leibowitz, M.D., Ph.D., Professor Honghua Li, Ph.D., Associate Professor Michael Newlon, Ph.D., Assistant Professor Stuart W. Peltz, Ph.D., Professor Sidney Peskta, M.D., Professor and Chairman Yacov Ron, Ph.D., Professor Yufang Shi, DVM, Ph.D., Professor Victor Stollar, M.D., Professor Nancy Woychik, Ph.D., Associate Professor Faculty Resident at CABM Arnold B. Rabson, M.D., Professor Aaron J. Shatkin, Ph.D., Professor Faculty (Coterminus) Philip Furmanski, Ph.D., Professor Emeritus Professors Harriet Rouse, Ph.D., Emeritus Professor William A. Strohl, Ph.D., Emeritus Professor Joint Appointments Bruce C. Byrne, Ph.D., Adjunct Professor of Medicine and Molecular Genetics,

Microbiology and Immunology Kiron M. Das, M.D., Ph.D., F.R.C.P., Professor of Medicine and Molecular Genetics,

Microbiology and Immunology Ellen C. Ebert, M.D., Associate Professor of Medicine and Molecular Genetics,

Microbiology and Immunology Janusz J. Godyn, Ph.D., Associate Professor of Pathology and Laboratory Medicine

and Molecular Genetics, Microbiology and Immunology Alice B. Gottlieb, M.D., Ph.D., Professor of Medicine and Molecular Genetics,

Microbiology and Immunology

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Joint Appointments, Cont'd Suhayl Dhib-Jalbutm M.D., Professor of Neurology and Molecular Genetics,

Microbiology and Immunology Christopher G. Janson, M.D., Adjunct Assistant Professor of Surgery and Molecular

Genetics, Microbiology and Immunology Edmund C. Lattime, Ph.D., Professor of Surgery and Molecular Genetics, Microbiology

and Immunology Paola Leone, Ph.D., Associate Professor of Surgery and Molecular Genetics,

Microbiology and Immunology Randall D. McKinnon, Ph.D., Associate Professor of Surgery and Molecular Genetics,

Microbiology and Immunology M. Maral Mouradian, M.D., Professor of Neurology and Molecular Genetics,

Microbiology and Immunology Daniel A. Notterman, M.D., Professor of Pediatrics and Molecular Genetics,

Microbiology and Immunology Karel F. Raska, Jr., M.D., Ph.D., Clinical Professor of Pathology and Adjunct Professor

of Molecular Genetics, Microbiology and Immunology Michael Reiss, M.D., Professor of Medicine and Molecular Genetics, Microbiology and

Immunology Roger K. Strair, M.D., Ph.D., Associate Professor of Medicine and Adjunct Associate

Professor of Molecular Genetics, Microbiology and Immunology Moti L. Tiku, M.D., MBBS, Associate Professor of Medicine and Adjunct Associate

Professor of Molecular Genetics, Microbiology and Immunology Adjunct Faculty Jeffry Cook, Ph.D., Adjunct Assistant Professor Chiann-Chyi Chen, Ph.D., Adjunct Assistant Professor Mei-Ling Li, Ph.D., Adjunct Assistant Professor Srijata Sarkar, Ph.D., Adjunct Assistant Professor Lee Ann Schein, Ph.D., Adjunct Instructor Hui-Yun Wang, Ph.D., Adjunct Assistant Professor Junxia Xie, Ph.D., Adjunct Assistant Professor Jian-Nian Zhou, Ph.D., Adjunct Assistant Professor Volunteer Adjunct Faculty Sefik S.Alkan, Ph.D., Adjunct Professor Edward Arnold, Ph.D., Adjunct Professor David P. Beck, Ph.D., Adjunct Professor C. Thomas Caskey, M.D., Adjunct Professor Graham R. Cleaves, Ph.D., Adjunct Assistant Professor Dalia Cohen, Ph.D., Adjunct Associate Professor Jeffry Cook, Ph.D., Adjunct Assistant Professor Wendy D. Cornell, Ph.D., Adjunct Assistant Professor

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Volunteer Adjunct Faculty, cont'd Lori R. Covey, Ph.D., Adjunct Associate Professor Gorbadhan Das, Ph.D., Adjunct Professor Jonathan D. Dinman, Ph.D., Adjunct Associate Professor Jürgen Drews, M.D., Adjunct Professor Arthur M. Felix, Ph.D., Adjunct Professor Robert C. Gallo, M.D., D.Sc., Adjunct Professor Gianni Garotta, Ph.D., Adjunct Professor Carlos I. Gonzalez, Ph.D., Adjunct Assistant Professor Florence C. Kimball, Ph.D., Adjunct Associate Professor King-Teh Lin, Ph. D., Adjunct Instructor George E. Mark III, Ph.D., Adjunct Professor Fred Mermelstein, Ph.D., Adjunct Assistant Professor Margaret Prescott, Ph.D., Adjunct Associate Professor Abbas Rashidbaigi, Ph.D., Adjunct Assistant Professor Hugh Rosen, M.D., Ph.D., Adjunct Assistant Professor John J. Siekierka, Ph.D., Adjunct Assistant Professor Leonard H. Sigal, M.D., Adjunct Professor Michael Steinmetz, Ph.D., Adjunct Professor Peter Tolias, Ph.D., Adjunct Professor George B. Weiss, Ph.D., Adjunct Professor Lawrence P. Wennogle, Ph.D., Adjunct Assistant Professor Carol J. Wilusz, Ph.D., Adjunct Assistant Professor Junxia Xie, Ph.D., Adjunct Assistant Professor

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Research Associates, Postdoctoral Appointees Xiangfeng Cui, Ph.D. Md. Anwar Hossain, Ph.D. Christopher Krause, Ph.D. Raj Prasad, Ph.D. Erwei Sun, Ph.D. Irina Tereshchenko, Ph.D. Natalia Zamolodchikov, Ph.D. Predoctoral Trainees Lili Banihashemi Hector Caban Sandra Chesoni Radharani Duttagupta Danielle Frikker Yvette Green Malavika Gupta Guohong Hu Jin-Hyung Lee Willey Liao Sofiya Micheva-Viteva Sayandip Mukherjee Pedro Ortiz Sedide Ozturk Bradley Phelan Meredith Prysak Estelle Ruidiaz Kristina Sutphen Zhihong Yang Jiangling Zhuang Part-time Laboratory Staff Yan Hu Xi Jiang, M.S. Ling Ma Sheila Mazar Beverly Novembre Nomi Ron, M.S

Full-time Laboratory Staff Monika Anand, Ph.D. Marco Azaro, Ph.D. Chiann-Chyi Chen, Ph.D. Nyam-Osor Chimgee, Ph.D. Jyoti Das, M.S. Satish Devadas, Ph.D. Regina Felder-Gibbions Randi Foster, M.S. Richeng Gao, M.S. Stephane Gross, Ph.D. Lara Izotova, Ph.D. Danny Tu Khounh, Ph.D. Youngsun Kim, Ph.D. Scott Kinzy, B.S. Florence LeRoy, Ph.D. Xiangyang Li, M.S. Baisong Liao, Ph.D. Catherine Liu, M.S Jiebo Lu, Ph.D. Minjie Luo, Ph.D. Olga Mirochnitchenko, M.S. Annmarie Pacchia, Ph.D. Sreemanta Pramanik, Ph.D. Raj Prasad, Ph.D Cheryl Rebsch, B.S. Arthur Roberts, M.S. Barbara Schwartz, M.S. Li Shen, M.S. Rory Ulloque, B,S, Xiao-Juan Xu Qifeng Yang, Ph.D. Zengrong Yuan, Ph. D. Liying Zhang, M.D.

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DEPARTMENTAL ACTIVITIES

Appointments

Gobardhan Das, Ph.D., Appointment as Adjunct Professor of Molecular Genetics, Microbiology and Immunology, effective 9/13/04

Change in Status Annmarie Pacchia, Ph.D., Research Teaching Specialist II to Research Teaching

Specialist I, effective 12/1/2004 Jianling Zhuang, Graduate Student to Research teaching Specialist IV, effective

4/15/2005 Jeffry Cook, PH.D., Adjunct Assistant Professor to Volunteer Adjunct Assistant

Professor, effective 2/28/05 Junxia Xie, PH.D., Adjunct Assistant Professor to Volunteer Adjunct Assistant

Professor, effective 2/28/05

Students Receiving Ph.D. Degrees Jianling Zhuang, defended 3/16/2005 Radharani Duttagupta, defended 4/14/2004 Jin Hyung Lee, defended 1/14/2005

Departures/Transfers

Marco Azaro, left 3/22/2005 Charnel Bohn, left 5/20/2005 Jessica Hamilton, left 9/27/2004 Youngsun Kim, left 2/28/2005 Jin Hyung Lee, left 2/28/2005 MIngie Luo, left 3/1/05 Jiebo Lu, left 11/12/2004 Anupama Mehta, left 7/9/2004 Nyan-Osor Chimgee, left 11/05/2004 Raj Prasad, left 3/30/2005

Li Shen, left 10/1/2004 Nancy Stevens, left 2/28/2005 Chris Suleski, left 9/10/2004 Erwei Sun, left 12/31/2004 Irina Tereshchenko, left 10/29/2004 Hui-Yuan Wang, left 3/11/2005 Gang Yue, left 1/3/2005 Qifeng Yang, left 3/1/2005 Jian-Nian Zhou, left 2/29/04

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New Employees

Full-time Administrative Staff Jamie Carr 6/6/2005 Andrea Finamore 2/14/2005 Full-time Laboratory Staff Yoshifumi Kobayashi 6/6/2005 Manjing Pan 5/2/2005 John Spychala 8/8/2004 Guangwu Xu 11/23/2004

Predoctoral Trainees Lili Banihashemi Kelvin Caban Jennifer Defren Frances Gratacos Malavika Gupta Anna Knapinska Rose Lee Mohan Liu Guangwen Ren

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DEPARTMENTAL COMMITTEES

Vice Chairman

Victor Stollar

Standing Advisory Committee Jerome Langer

Michael Leibowitz Victor Stollar

Core Facility Committee Terri Goss Kinzy Lee Ann Schein

Barbara Schwartz Rick Wernoski

Seminar Committee Gary Brewer

Terri Goss Kinzy Nancy Stevens Rick Wernoski Nancy Woychik

Faculty Recruitment Committee Arnold Rabson

Yacov Ron Yufang Shi

Nancy Woychik

Renovations Committee Terri Goss Kinzy Jerome Langer Rick Wernoski

MGMI Retreat Committee Gary Brewer

Nancy Stevens Victor Stollar

Rick Wernoski

Equipment Committee Donald Dubin

Terri Goss Kinzy Michael Leibowitz Barbara Schwartz

Rick Wernoski

Holowczak Memorial Committee Paul Copeland Nancy Stevens Victor Stollar

Rick Wernoski

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Activities of

MGMI

Faculty Members

2004-2005

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Gary Brewer, Ph.D. Research Activities Dr. Brewer’s research involves the study of proto-oncogene, cytokine, and growth factor messenger RNA stability and its regulation. Multiple sequence elements control the levels of these mRNAs. The best characterized are A+U-rich elements (AREs) present in the 3’-untranslated regions of subsets of these mRNAs. Other elements lie in the coding region and/or 5’ untranslated region. Our main focus is how RNA-binding proteins that recognize these elements target cognate mRNAs for degradation. We utilized RNA interference as a genetic tool to reduce expression of a family of proteins known as insulin-like growth factor mRNA binding proteins (IMPs). This protein family associates with a number of proto-oncogene and growth factor mRNAs, including MYC and IGF-II. Dr. Brewer found that IMP1 binds to IGF-II mRNA and decreases both IGF-II production and cell proliferation. By contrast, IMP3 binds IGF-II mRNA and promotes its translation. Thus, these two proteins act in an antagonistic fashion to provide positive and negative control of cell proliferation. Highlights of the Year Dr. Brewer published two seminal papers reporting the yin/yang regulation of cellular proliferation by IMP1 and IMP3. These papers address the mechanisms as to how the antagonistic actions of these two RNA-binding proteins control proliferation. Publications Liao, B., Patel, M., Hu, Y., Charles, S., Herrick, D.J., and Brewer, G. Targeted

knockdown of the RNA-binding protein CRD-BP promotes cell proliferation via an IGF-II-dependent pathway in human K562 leukemia cells. J. Biol. Chem., 2004; 279: 48716-48724.

Liao, B., Hu, Y., Herrick, D.J., and Brewer, G. The RNA-binding protein IMP-3 is a

translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells. J. Biol. Chem. 2005; 280; 18517-18524.

Presentations “Killing the Messenger: mRNA Degradation in Mammalian Cells”. Delivered January14,

2005 at the Department of Molecular Biology and Biochemistry, University of Ottawa, Canada.

“Killing the Messenger: mRNA Degradation in Mammalian Cells. Delivered April 26,

2005 at the Nebraska Redox Biology Center, University of Nebraska, Lincoln, NE Teaching MGMB 6000, Microbiology & Immunology , 1 lecture hours

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MICR 9000, Research in Mol. Genetics, Virology, Cell Biol., Genetic Engineering Elective Contact Person

01:146:470+16:148:514, Advanced Cell Biology/Mol Biol of Cells , 6 lecture hours

MICMOLGEN 681:612, Lab Rotations , 60 laboratory hours Student mentor for four graduate rotation students BIOL 01:119:406, Research in Biology , 45 laboratory hours Mentor to four undergraduate students Graduate Student Committee Memberships Member, Preliminary Oral Examination for Peng Zhang (Welsh), July 28, 2004 Member, Thesis Examination Committee for Radharani Duttagupta (Peltz), April 14,

2005 Member, Preliminary Oral Examination for Brian Leibowitz (Cohick), April 22, 2005 Member, Preliminary Oral Examination for Jongjin Jung (Talaga), June 14, 2005

Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Reka Letso, Swati Gupta, Shakil Farooqui, Alexandria Wierzbowski, Sonia Agarwal,

Vickey Tsai, Yanan Zhou, Sri Adusumalli, student assistants Jiebo Lu, Baisong Liao, research associates Seminars Sponsored Dr. Myriam Gorospe, National Institute on Aging – NIH, “Journey Matters: Ribonucleoprotein Partnerships Regulating mRNA Turnover and Translation”, November 9, 2004. Administrative Committees Departmental Member, Student Affairs and Academic Standing Committee of Graduate Program in

Molec. Genetics and Microbiology Member, Departmental Seminar Committee Member, Retreat Committee, Department of Molecular Genetics, Microbiology, &

Immunology University Director, Tutoring Program for Graduate School of Biomedical Sciences (GSBS) Federal/State Appointments Reviewer for National Science Foundation and U.S./Israel Binational Science

Foundation

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Community Involvement on Behalf of University or Medical School Sponsor for Swati Gupta, Johns Hopkins University, JHU Research in Biology, Summer,

2004, 2005 Sponsor for Danielle Turrin, Rutgers University, Research in Genetics, 2004-2005 Sponsor for Holly Porter, Rutgers University, Honors Research in Biology, 2004-2005 Sponsor for Reshma Patel, Rutgers University, Research in Genetics, 2004-2005 Sponsor for Neha Das, Rutgers University, Research in Biology, 2005 Sponsor for Joanna Mercado Cruz, Pontifical Catholic University in Puerto Rico, RISE

Program, Summer 2004 Sponsor for Franchesca Fiorito, University of Puerto Rico - Rio Piedras, RISE Program,

Summer 2005 Sponsor for Sonya Agarwal, Rutgers University Work/Study Program, 2005

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Paul R. Copeland, Ph.D. Research Activities

Incorporation of selenocysteine Selenocysteine is a unique amino acid that is incorporated specifically into a select group of essential proteins. This process represents a modification of the standard protein synthetic machinery in that it requires the utilization of a novel translation elongation factor (eEFSec), a selenocysteine insertion sequence (SECIS) element in the 3' untranslated region (UTR) of selenoprotein mRNAs, and a novel SECIS binding protein termed SBP2. These factors act in concert to alter the coding potential of specific in-frame stop codons (UGA) by specifying the insertion of selenocysteine at that site. One of the goals of our work is to understand the interplay between SBP2 and the translation machinery. Since SBP2 is a limiting factor required for Sec incorporation, it is central to the regulation of the synthesis of selenoproteins , many of which are known to play critical roles in cellular defense from oxidation. As a result, SBP2 will be a key target for methods designed to increase the beneficial properties of selenoproteins including the prevention of DNA damage in carcinogenesis and oxidation of pathogenic lipids involved in atherosclerosis. We seek to understand the detailed function of SBP2 by studying its specific interaction with ribosomes and its interaction with the machinery that would ordinarily dictate the termination of translation at selenocysteine (UGA) codons. Our preliminary studies indicate that SBP2 specifically interacts with ribosomal RNA from a variety of species, indicating that the SECIS element may have evolved from highly conserved rRNA structures. This study will combine the utilization of mammalian cells and the yeast S. cerevisiae in order to thoroughly explore this interaction while exploiting the unique benefits of each system. Specifically, we are using mammalian rRNA fragments to probe the binding characteristics of SBP2. This is being done in combination with an analysis of SBP2 binding to intact yeast ribosomes in vitro and in vivo. In addition, we will directly assess the role of SBP2 in preventing termination at selenocysteine codons by analyzing Sec incorporation from efficient and inefficient templates. The information we obtain about the function of SBP2 will be used to develop a detailed model for Sec incorporation that should shed light on the basic mechanism of translation termination as well as enable us to identify components of the system that can be manipulated in order to optimize selenoprotein synthesis.

Selenium and Cancer In 1996, it was reported that dietary selenium supplementation resulted in a significant reduction in total cancer mortality and specifically reduced the incidence of lung, colorectal and prostate cancers (Clark et al., 1996). Increased dietary selenium is either acting through the increased production of selenoproteins or through the action of selenium-containing small molecules that have unknown function. Since many selenoproteins provide a protective barrier against oxidative damage to cellular components, including DNA, we believe that a significant part of the chemoprotective effect of selenium supplementation is the result of an increase in selenoprotein expression. If increased dietary selenium is primarily functioning through the selenoprotein pathway, then prostate cancer cells are likely to have altered selenoprotein expression. Indeed, it has been observed that at least one selenoprotein

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is dramatically reduced in prostate cancer. It is therefore of great importance to determine whether selenoprotein synthesis is a central part of the protective action of selenium, and thus a study of the regulation of this process is a critical part of discovering the mechanism of selenium chemoprevention. Specifically, this study will assess the effects of both increased selenium and increased selenoprotein synthetic capacity on cadmium-induced carcinogenesis of normal prostate cells in culture. In addition, to address the regulation of selenoprotein synthesis during prostate oncogenesis, we will identify the point of regulation responsible for the dramatic down-regulation of selenoproteins in prostate cancer as well as determine the contribution of the selenocysteine incorporation machinery to this regulation. Within the context of selenoprotein synthesis, it is important to note that all of the required factors may not be known. One of the ultimate goals of this research is to identify means by which to modulate the efficiency of selenoprotein synthesis, ideally in a selenoprotein-specific manner. Toward this end we are studying the SBP2-like protein (SLP), which is preferentially expressed in human prostate. This protein has no known function, but is similar enough to SBP2 to strongly suggest that it is involved in selenocysteine incorporation. Our study will provide evidence for the contribution of SLP to selenocysteine incorporation in order to provide a foundation for future work that will dissect its apparently prostate-specific function. Highlights of the Year This year Dr. Copeland has published his findings that SBP2 functions as a monomer, thus complicating its dual role as a SECIS binding protein and a ribosome binding protein. Interestingly, a wild-type but not a mutant SECIS element is able to effectively compete with the SBP2 ribosome interaction, indicating that SBP2 cannot simultaneously interact with the ribosome and the SECIS element. This data also supports the hypothesis that SBP2 interacts with one or more kink turns on 28S rRNA. Based on these results Dr. Copeland proposed a revised model for selenocysteine incorporation where SBP2 remains ribosome bound except during selenocysteine delivery to the ribosomal A-site. Publications Peer Reviewed Copeland, P.R. (2005) Making sense of nonsense: the evolution of selenocysteine

usage in proteins. Genom. Biol. 6:221. Kinzy, S.A., Caban, K. and Copeland, P.R. (2005) Characterization of the SECIS

binding protein 2 complex required for the co-translational insertion of selenocysteine in mammals. Nucl Acid Res. 33:5172-5180.

Abstracts Poster: “Investigation of the chemopreventive properties of selenium in the prostate”

presented at Selenium Biochemistry 2003, Bethesda, MD. December, 2003 Poster: “Selenium and Prostate Cancer” presented at ABRCMS San Diego, CA. October,

2003.

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Presentations January, 2004. Deans’ Lunch Robert Wood Johnson Medical School (2004) “The

nonsense about selenium and the 21st amino acid.” Piscataway. Seminars Sponsored October, 2004, Donna Driscoll, Cleveland Clinic Foundation April, 2005, Raymond Burk, Vanderbilt University Teaching Biochemistry 501 Seminar Course Microbiology and Immunology mgmb6000 Molecular Biology Journal Club – director Obtained Funding for Research Education for Teachers pilot program to be implemented summer 2004 Graduate Student Committee Memberships Pedro A. Ortiz (MGM) Kristina Sutphen (MGM) Hector Caban (MGM) – mentor Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Hector Caban, Graduate Student Kelvin Caban, Graduate Student Cheryl M. Rebsch, RTS V Scott Kinzy, RTS III Anupama Mehta, Laboratory Technician Kathleen Wright, Undergraduate Student Ruchira Ranaweera, Undergraduate Student Administrative Committees Departmental Holowczak Memorial Committee Chairman, Department Website Committee

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RWJMS Research Day Committee Graduate Admissions Committee Community Involvement on Behalf of University of Medical School Invited Judge at the Annual Biomedical Research Conference for Minority Students,

San Diego Judge: NJ regional science fair, Rutgers University Editing/Consulting Reviewer for: Molecular and Cellular Biology RNA PLoS PNAS

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Joseph P. Dougherty, Ph.D. Research Activities Research in our laboratory focuses upon studying retroviral replication as well as the design and development of retroviral vectors for gene therapy and anti-HIV-1 drug discovery. In addition, we have recently expanded our work to gene expression particularly as it pertains to the immune system. A more detailed description of our most recent work follows. Latency model for antiviral drug development aimed at eliminating HIV infection. The advent of highly active antiretroviral therapy (HAART), which involves the use of three or more antiretroviral drugs, has led to a significant improvement in the care and survival of patients infected with HIV-1. However, even after long-term suppression of viral replication with HAART, the virus rapidly rebounds after therapy is discontinued. A key contributor to viral rebound appears to be a reservoir of latently infected cells, including CD4+ memory T cells. The half-life of the latently infected population is quite long, and it is estimated that it would take over 60 years of HAART to eliminate this population. Therefore, life-long HAART would be required to control infection in patients which, given adverse side-effects and the development of drug-resistant strains, is not optimal.

A potentially fruitful approach to eliminating virus infection would be to identify small molecules with pharmacological properties that allow these molecules to reach hard to access latent reservoirs in order to activate latent proviruses. As part of this strategy, the patients would remain on HAART to prevent new infections, and the infected cells from which the latent proviruses are activated would die due to cytotoxic effects of viral expression and/or because of targeting by the immune system which can recognize the cells that begin to express the viral proteins.

There is precedent for a small molecule that can activate latent HIV-1 proviruses. Valproic acid (VPA) is a histone deacetylase (HDAC) inhibitor, which is presently in clinical use as an anticonvulsant agent. It had previously been shown that HDAC1 can mediate chromatin remodeling and inhibit HIV-1 gene expression in CD4+ T cells consequently reducing virus production. This prompted experiments to be performed to determine whether VPA could activate latent virus. First, VPA was examined for its ability to activate latent virus in a cell culture system, and it was found that treatment with VPA did promote virus production. This work led to a recent clinical study with four HIV-1 infected patients responding well to HAART. The patients were treated with VPA for 4 to 6 weeks, and the frequency of latent virus infection was measured using a limiting dilution protocol in which resting CD4+ T cells were obtained from the patients before and after VPA treatment and activated ex vivo. The trial indicated that 3 of 4 patients demonstrated a significant decrease in the number of latently infected T cells. Although the latent virus was not totally cleared from any of the patients, it indicates that an approach using pharmacological agents might ultimately be developed that would result in clearance of the virus from infected individuals. Thus, this is an opportune time to identify other small molecules capable of activating latent HIV-1.

We devised a cell-based assay adaptable for high throughput screening (HTS) of compounds that can efficiently activate expression of late HIV-1 genes and thus

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stimulate the viral outgrowth from the latent reservoir. Our system is based on a clonal cell line isolated after transduction of a human T cell line, SupT1, with a recombinant HIV-1 vector. The vector was constructed in a way that allows expression of a reporter, secretable alkaline phosphatase (SEAP), as a late viral gene due to its insertion in the position of the start codon of HIV-1 envelope. SEAP production can be monitored by a sensitive chemiluminescent reaction, which can be adapted for use in HTS. This is a sensitive system that meets biosafety requirements since no replication-competent virus can be produced during the screening process. The latent provirus within the cells could be reactivated by various agents including TNF-α, phorbol 12-myristate 13-acetate (PMA), and VPA. It is also noteworthy that a strong and reproducible signal was detected in 96-well and 384-well formats. Thus, we have developed a latency system that can be used for new drug discovery as well as for studying the mechanism of HIV-1 latency, and we are in the process of HTS. Retroviral Recombination. The basic models for retroviral reverse transcription have remained unchanged for more than twenty-five years. Every model depicts DNA synthesis as being continuous using a single RNA template. However, we have obtained data indicating that this is not the case. We propose that the leading strand switches from one RNA template to the other RNA template multiple times during each and every cycle of replication. To date, the most compelling evidence comes from our work examining HIV-1 recombination. The data suggest that proviral progeny of heterozygous virions produced by cells harboring two genetically distinct retroviruses are all recombinant. However, this was in sharp contrast to previously reported data from the gammaretrovirus murine leukemia virus (MLV). A significant difference in the recombination rates between HIV-1 and MLV was previously reported, with the former being 10 to 100 times more recombinogenic. It was possible that preferential copackaging of homodimers in the case of MLV led to underscoring of its rate of recombination. To reexamine the recombination rates for MLV, experiments were performed to control for non-random copackaging of viral RNA, and it was found that MLV and HIV-1 exhibit similar recombination rates. Our work suggests that the basic model of retroviral reverse transcription should be modified to reflect that template switching occurs multiple times during minus-strand DNA synthesis. This also implies that retroviral genes are essentially unlinked, indicating that retroviral replication is genetically akin to orthomyxovirus reassortment with one difference being that the breakpoints are random for retroviruses while they are defined by the segmented genomes of orthomyxoviruses. If recombination always occurs during retrovirus replication, this would make the process of recombination a core component of the virus lifecycle. A novel function for RNase L in regulating translation termination. The antiviral and antiproliferative effects of interferons are mediated in part by the 2-5A/RNase L RNA decay pathway. RNase L is an endoribonuclease requiring 2’-5’ oligoadenylates (2-5A) to cleave single-stranded RNA. In collaboration with Dr. Stuart Peltz, we have found evidence that RNase L might have a role in translation. We identified and characterized the translation termination factor eRF3/GSPT1 as an interacting partner of RNase L. We demonstrated that interaction of eRF3 with RNase L leads to both increased translation readthrough efficiency at premature termination codons and

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increased +1 frameshift efficiency at the antizyme +1 frameshift site. Based on these results, it appears that RNase L plays a role in regulating gene expression by modulating the translation termination process. Highlights of the Year Developed a model of viral latency that can be used for anti-HIV drug discovery aimed at purging virus infection Discovered that the recombination rate of disparate retroviruses is very high suggesting that all retroviruses including HIV are always subject to recombination crossovers during each and every cycle of replication Discovered that the translation termination factor eRF3 interacts with RNase L, which is important in mediating interferon activity, suggesting that RNase L plays a role in regulating gene expression by modulating the translation termination process Publications Duttagupta, R., B. Tian, C.J. Wilusz, D.T. Khounh, P. Soteropolous, M. Ouyang, J. P.

Dougherty, and S.W. Peltz. Global analysis of Pub1p targets reveals a direct correlation between binding and stability for specific subsets of cellular messages. Molecular and Cellular Biology, In Press.

Le Roy, F., T. Salehzada, C. Bisbal, J.P. Dougherty, and S.W. Peltz. A newly

discovered function for RNase L in regulating translation termination. Nature Structural and Molecular Biology 12(6):505-12 (2005).

Teaching Microbiology & Immunology (Medical Students) - 01:680:544:545 Graduate Student Committee Memberships Advisor for: Rose Lee Sofiya Micheva-Viteva Sayandip Mukherjee Bradley Phelan Jiangling Zhuang (received PhD) Committee member for: Radha Duttagupta (received PhD) Danielle Frikker (received PhD) Guohong Hu (received PhD)

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Willey Liao Laboratory Staff Radha Duttagupta Md. Anwar Hossain Rose Lee Florence LeRoy Willey Liao Sofiya Micheva-Viteva Sayandip Mukherjee Annmarie Pacchia Bradley Phelan Danny Tu Khounh Jiang Xi Jiangling Zhuang Administrative Committees Departmental Director of the Graduate program in Molecular Genetics, Microbiology & Immunology Director of HIV Culture Facility University Executive Committee for the Molecular Biosciences Program (UMDNJ/Rutgers Joint

Graduate Program) Chairman of Institutional Biosafety Committee Editing/Consulting Reviewed manuscripts for the Journal of Virology, Virology, the Journal of Virological

Methods, and the Proceedings of the National Academy of Sciences.

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Donald T. Dubin, M.D. Research Activities Dr. Dubin has stopped active laboratory research. I continue to follow the current literature on molecular mechanisms of antibiotic resistance in staphylococci and pneumococci. Administrative Committees Departmental Core Facility Committee Student Affairs and Academic Standing Committee (Chairman). RWJMS Admissions Committee, Including Steering Sub-Committee and Secondary Selection

Committee.

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Fig. 1: Translation elongation in S. cerevisiae, highlighting the role of eEF1A in aa-tRNA delivery (A), eEF2 in translocation (C), eEF3 in E-site function (A) and eEF1Bαγ in nucleotide exchange (E).

Translocation

Peptidyltransfer

eEF2 aa-tRNAbinding

eEF1Bαγ

GTP

GDP

GTP

eEF1A

Codon recognitionGTP hydrolysis

GTP

GDP

aa

aa

OH

GTPOHeEF3 aa

A

B

C

D

E

APE

ATP

OH

Terri Goss Kinzy, Ph.D. Research Activities The goal of the work in the Kinzy laboratory is to understand the structural and functional basis of G-protein regulation and post-transcriptional mechanisms that regulate gene expression. The components of the Translation Elongation apparatus in yeast, from soluble protein factors to the ribosome, allow an integrated approach to these questions. These components are targets for antibiotics and antifungals; mutant forms and inappropriate expression of these proteins are found in several human carcinomas, and mutations in several components affect the accuracy and efficiency of protein synthesis and viral replication. We are applying complementary genetic, molecular, biochemical and structural techniques to dissect the mechanism of events occurring during protein synthesis, the physical and functional interaction of Elongation Factors (eEFs) with other factors that regulate gene expression, and the interaction between this G-protein and its GTPase activating factor (GAP), the ribosome. The eEF1 protein complex is prototypical of all G-proteins, such as the oncogene Ras, and as such is regulated by a classic "GTPase" switch mechanism. The GTP-dependent activity of eEF1A is to deliver aminoacyl-tRNA to the ribosome and sense the accuracy of this process. The guanine nucleotide exchange factor (GEF), eEF1Balpha, is essential in yeast and responsible for catalyzing the exchange of GDP for GTP to maintain the pool of active protein. Using a genetic system devoid of the eEF1Balpha protein allows us to manipulate eEF1A without its GEF to understand the regulation of G-protein activity, and mutant forms of eEF1Balpha allow us to dissect the mechanism of guanine nucleotide exchange in vitro and the consequences of changes in this protein’s activity in vivo. Lastly, the eEF1Bgamma subunit affects the sensitivity of the cell to oxidative stress. Current work is addressing the implications of this finding in post-transcriptional control using a proteomics approach. The two other factors involved in elongation, eEF2, the translocase, and eEF3, a fungal specific factor, are integrated with the above work to fully dissect the mechanisms of protein synthesis and to better understand their potential as drug targets. We have worked in collaboration with Dr. Gregers Andersen to perform X-ray crystallographic studies of the eEF1 subunits, eEF2 and eEF3.

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Highlights of the Year In the past year the understanding of the role of the translation elongation factors has extended beyond their canonical role in protein synthesis. Several of the subunits have been linked, through Dr. Kinzy’s work and work with her collaborators, to cellular processes such as proteosome dependent protein degradation and the regulation of the actin cytoskeleton. Additionally, the regulatory role of the guanine nucleotide exchange factor complex is now linked to the specific post-transcriptional regulation that occurs in response to oxidative stress. Publications Andersen, C.F., Anand, M., Boesen, T., Van, L.B., Kinzy, T.G. and Andersen, G.R.

(2004) Purification and crystallisation of the yeast translation elongation factor eEF3, Acta Crystallogr. D Biol. Crystallogr. D60: 1304-1307.

Olarewaju, O., Chowdhury, W., Ortiz, P.A., Chatterjee, I., and Kinzy, T.G. (2004) The

translation elongation factor, eEF1B plays a role in the oxidative stress response pathway, RNA Biology 1:12-17.

Chuang, S-M., Lambertson, D., Chen, L., Anand, M., Kinzy, T. G. and Madura, K.

(2005) Proteasome-mediated degradation of co-translationally damaged proteins involves the translation elongation factor eEF1A, Mol. Cell. Biol. 25:403-413.

Copeland, H.L. and Kinzy, T.G. (2005) Development and evaluation of a peer-tutoring

program for graduate students, Biochem. Mol. Biol. Ed. 33:86-90. Komar, A.A., Gross, S.R., Barth-Baus, D., Strachan, R., Hensold, J.O., Kinzy, T.G. and

Merrick, W.C. (2005) Novel characteristics of the biological properties of the yeast Saccharomyces cerevisiae initiation factor elF2A, J. Biol. Chem. 280:15601-11.

Abstracts: Kinzy, T.G., Anand, M., Green, Y.R., Gross, S., Ortiz, P.A., Ozturk, S. and Ulloque, R.

Cellular Partners of Translation Elongation Factor 1A, ACS Central Regional Meeting, Indianapolis IN, 2004.

Ortiz, P.A. and Kinzy, T.G. Regulation of Translation Elongation Factor 2 Levels in

Yeast, Translational Control, Cold Spring Harbor, N.Y, 2004. Anand, M., Balar, B. and Kinzy, T.G. Mapping the Interaction of the Fungal Specific

Translation Elongation Factor eEF3 with Itself, eEF1A and Ribosomes, Translational Control, Cold Spring Harbor, N.Y, 2004.

Ortiz, P.A., Ulloque, R., and Kinzy, T.G., Mutations in the anticodon mimicry domain of

translation elongation factor 2 affect translational fidelity, Annual Biomedical Research Conference for Minority Students, Dallas, TX, 2004.

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Ortiz, P.A., Ulloque, R., and Kinzy, T.G., Mutations in the anticodon mimicry domain of

translation elongation factor 2 affect translational fidelity, 6th Annual Research Day, Robert Wood Johnson Medical School, New Brunswick, NJ, 2004.

Ortiz, P.A., Ulloque, R., and Kinzy, T.G., Mutations in the anticodon mimicry domain of

translation elongation factor 2 affect translational fidelity, 4th Annual New England Science Symposium, Boston, MA, 2005.

Copeland, H.L. and Kinzy, T.G. Development and Evaluation of a Peer-Tutoring

Program for Graduate Students, UMDNJ Master Educator Guild Symposium, Piscataway, NJ 2005.

Ortiz, P.A., and Kinzy, T.G., Analysis of the regulation of translation elongation factor 2

in yeast, 2005 Annual Retreat on Cancer Research in New Jersey, Princeton, NJ, 2005.

Balar, B., Anand, M. and Kinzy, T.G. Dissecting the Function and Mechanism of Fungal

Specific Translation Elongation Factor 3, 2005 Annual Retreat on Cancer Research in New Jersey, Princeton, NJ, 2005

Ozturk, S. Novel eEF1alpha mutations that are bypass suppressors of the translation

elongation nucleotide exchange factor eEF1Balpha, 2005 Annual Retreat on Cancer Research in New Jersey, Princeton, NJ, 2005

Web site annotation: Anand, M., Balar, B.A., Gross, S., Ortiz, P.A., Ozturk, S., Pittman, Y.R., Ulloque, R.,

Kinzy, T.G., (2005) The Reactome: Translation Elongation. http://www.reactome.org/cgi-bin/frontpage.

Presentations “Leadership Training for Women, Build Your Own Ladder” RWJMS Faculty March

31,2005 “Post-Transcriptional Control of Gene Expression, Anti-Viral and Anti-Fungal Targets in

the Protein Synthetic Apparatus” RWJMS Students Interested in Research 11/30/04

“Link between the translation elongation factor, eEF1 Bgamma and gene expression in

the stress response pathway” NIEHS Center at RWJMS Rutgers12/3/04 Invited Speaker: SUNY Downstate “Integrated Genetic and Biochemical Analysis of

Translation Elongation in Yeast” 4/28/05 Invited Speaker: Univ. Maryland ”Integrated Genetic and Biochemical Analysis of

Translation Elongation in Yeast” 2/23/05

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Invited Speaker: Univ. North Carolina “The Fungal Specific Translation Elongation Factor 3” 4/19/05

Teaching Medical Microbiology Rutgers Intro. to Mol. Biol. and Biochemistry Research (115:315) The Application of Fungal Systems to Mol. & Cell. Bio. MICR 5683 Molecular Medicine MICR-6003; Rutgers 16:681:530 Ethical Scientific Conduct (IDST 5000 RU 16:115:556) Director, graduate student peer tutoring program Honors 2004 Woman of the Year in Medicine, Somerset County, New Jersey Seminars Sponsored May 10, 2005 Sandra Weller PhD Univ. Conn. Graduate Student Committee Memberships Thesis Committee Member: Sanaz Oghlidos (Rutgers CDB) Barbara Siminovich-Blok (RWJMS Biochem.)

Radharani Duttagupta (RWJMS MGMI) Committee Member:

Carmela Palmero (RWJMS Pharm) Mariela Reyes-Reyes (RWJMS Biochem) Tyra M. Hall-Pogar NJMS BMB) Sandra Chesoni (RWJMS MGMI) Barbara Siminovich-Blok (RWJMS Biochem.) Shin-Wu Liu (Rutgers CDB)

Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Postdoctoral Appointees Monika Anand Ph.D. Stephane Gross Ph.D. Ph.D. Students Pedro Ortiz Yvette Green

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Sedide Ozturk Anthony Esposito Undergraduates Nidhi Sondhi Natalie Colimon Jessica Bockhorn Kristen Stashek Administrative Committees Department committees, task forces, projects MGMI Seminar Committee MGMI Graduate Program Admissions Committee MGMI Core Facilities Committee MGMI Renovations Committee MGMI Equipment Committee School committees, task forces, projects UMDNJ RWJMS Director, UMDNJ RWJMS DNA Synthesis and Sequencing Laboratory Cancer Institute of New Jersey Scientific Council Chairman, Research Committee Chairman, Core Facility Committee Laboratory Safely Committee Strategic Planning Steering Committee Co-organizer UMDNJ RWJMS/Rutgers Yeast Group Organizer CINJ Post-Transcriptional Control Focus Group NIEHS Center of Excellence Directors Internal Advisory Committee RWJMS Master Educators Committee RWJMS Web Site Advisory Committee NIEHS Center of Excellence Pilot Grant Review Committee Foundation of UMDNJ RWJMS Grant Review Committee RWJMS Department of Biochemistry Review Committee Organizer, High School Student & Teacher Programs Working Group UMDNJ GSBS UMDNJ-Rutgers University Pipeline Program: Advisement Coordinator Molecular Biosciences Qualifying Exam Committee Director of graduate student peer tutoring program University/Campus committees, task forces, projects UMDNJ Master Educator Guild UMDNJ Master Educator Guild Executive Committee

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University Central Committee, Subcommittee on Centers of Excellence UMDNJ Conflict of Interest Guideline Committee Invited focus group member for the Bildner Project "Developing Cultural Competency

Standards at UMDNJ" Community/state service Science Fair Judge, North Jersey Regional Science Fair and local science fairs Participant, NIEHS Summer Institute Invited judge, national Siemens Westinghouse Science Competition for high school

seniors Career Day Presenter, Bridgewater-Raritan Middle School 2004 Sponsored ACS SEED Program High School Student Executive Leadership in Academic Medicine (ELAM) Program for Women National

Advisory Committee Editing/Consulting Ad Hoc Reviewer: Nucleic Acids Research EMBO Journal EMBO Reports Journal of Biological Chemistry Genomics Genetics Molecular and Cellular Biology Biochemistry Protein Science European Journal of Biochemistry Molecular and General Genetics Service On Grant Review Panels, Study Sections, Committees: Reviewer, Wellcome Trust, U.K., Israel Science Foundation Member, N.I.H. Physiological Chemistry Study Section 2003-2007

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Jerome Langer, Ph.D. Highlights of the Year Dr. Langer applied for and received funding from the Alliance for Lupus Research for the design of inhibitors of Type I interferon that might be useful in the treatment of lupus (systemic lupus erythematosus). He is designing mutants of human interferon alpha that may be competitive antagonists of natural interferon; i.e., they will bind to the receptor, but will not trigger biological responses, and will block the activity of endogenous interferon. The project is a collaboration with Dr. Elizabeth Raveche (Dept. of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School). Dr. Langer also had several training grants renewed through the MORE division of NIGMS for graduate student support, including an “Initiative to Maximize Student Diversity” (IMSD) grant (Michael J. Leibowitz, PI; JA Langer, Co-PI and Program Director), and the AMSU-UMDNJ-GSBS Bridge to the Doctorate@ NIH/NIGMS R25 ABridge to the Doctorate@ Publications and Presentations Langer, J.A., Erenrich, E.S., Chaparro, M., Lustigman, B. and Leibowitz, M.J. (2004)

The Unified Plan: Interweaving M.S. and Ph.D. Bridge Programs with an IMSD Program. Abstract and Poster for the ABridges Program Meeting@, Minority Opportunities in Research Division, NIGMS, July 8-11, 2004. Denver, CO.

“Interferons and their receptors: From basis understanding to designing novel functions

and therapeutic applications”. Morehouse College, Atlanta, GA. 11/30/04. “Something old, something new: From Type I interferons to IFN-lambdas”. Alliance for

Lupus Research, “Interferons in Lupus” meeting (talk to investigators and scientific advisory board). December 2, 2004.

“The growing interferon family: from alpha to omega, and now lambdas.” Cornell

University/Sloan-Kettering/Hospital for Special Surgery Immunology Program Seminar Series, New York. Feb. 28, 2005.

“The dark side of Type I interferons? Testing its involvement in the pathogenesis of

lupus.” RWJMS Department of Medicine, Division of Rheumatology. June 20, 2005.

Teaching Microbiology & Immunology (RWJMS) Laboratory instructor. Molecular Biosciences Seminar (Spring 2005) Research/Technical Writing Seminar (NIH-sponsored undergraduate “Research in

Science & Engineering (“RISE”) at Rutgers/UMDNJ)”, Summer 2003 Program director and seminar leader

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Graduate Student Committee Memberships Danielle Frikker. Ph.D. thesis committee. Dept. of Molecular Genetics, Microbiology &

Immunology. Member. Thesis defense: 4/27/05 Guohong Hu. Ph.D. thesis committee. Dept. of Molecular Genetics, Microbiology &

Immunology. Member Eddie Perez. Ph.D. thesis committee. Dept. of Biochem (Ann Stock, advisor). Member. Xuelie (Julie) Song. Ph.D. thesis committee. Dept. of MGMI (Bill Moyle, advisor).

Member. Qualitying Examination committee (Ph.D.) Sedide Ozturk, Dept. of MGMI (Terri Kinzy,

advisor). Member. Distinction in Research M.D. students: Pawel Ochalski (final committee); Matthew

Wosnitzer (Faculty liaison). Administrative Committees Departmental MGMI Academic Standing Committee, Member MGMI Committee on Review, Member RWJMS and GSBS Faculty Secretary, RWJMS Community Service Strategic Planning Committee, RWJMS, member. Rules of Procedure Committee, RWJMS, member. Nominations Committee, RWJMS, member. RWJMS Executive Council, Member RWJMS review committee for grants for the Foundation of UMDNJ, member. RWJMS Search Committee for Director of Faculty Development: member RWJMS Distinction in Research Committee: member Student Academic Standing Committee, Consolidated Molecular Biosciences Graduate

Programs, Member. Rotation advisory committee, Consolidated Molecular Biosciences Graduate Programs,

Member RWJMS Committee on Research Integrity, member RWJMS Master Educators= Guild Advisory Committee on Faculty Development,

member. RWJMS-GSBS Master Educators’ Guild Nominating Committee: Chairman Molecular Biosciences Graduate Programs - interviewer Molecular Biosciences Graduate Programs - Minority Admissions Subcommittee,

member. “RISE at Rutgers/UMDNJ” - co-chair admissions committee

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University UMDNJ Master Educators= Guild, Member UMDNJ Middle States Accreditation Self-Study Committee, Member UMDNJ Strategic Planning Work Group, Member UMDNJ-AAUP Joint Faculty Peer Review Committee, Member UMDNJ Strategic Planning Retreat, Participant Member AAUP RWJMS Chapter, Executive Committee AAUP Council of Chapters (UMDNJ). Treasurer. Federal/State Appointments NIH/NIGMS Special Emphasis Panel/Scientific Review Group 2005/05 ZRG1 IMM-A

(50), “Bridges to the Future”. Grant reviewer. Feb. 22-23, 2005. Editing/Consulting Journal of Interferon & Cytokine Research, Editorial Board. Ad hoc reviewer: “Biochemistry”; “Proteins: Structure, Function and Bioinformatics”; “Journal of Molecular Biology”; “Journal of Interferon & Cytokine Research”

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Michael J. Leibowtiz, M.D., Ph.D. Research Activities Amyloids and prions of yeast and humans In a wide variety of biological systems, various proteins have been shown to be capable of folding into multiple stable conformations. In some cases, these include both the native conformation associated with normal biological function and an alternative amyloid or prion conformation, which may be non-functional or have been altered to show a gain of function resulting in a disease state or phenotypic change. Amyloids and prions are generally more stable to denaturation and proteolysis than the native protein, and have the ability to promote the refolding of native or partially unfolded protein into the altered amyloid or prion conformation. Amyloids were initially characterized as aberrant proteins accumulating in various neurodegenerative diseases, and prions were initially characterized as infectious proteins causing neurological diseases in mammals; however, in a wide spectrum of organisms, including humans and yeast, prions and amyloids can result in a variety of phenotypic effects on the cells in which they occur, and have been characterized both as etiologic agents of disease and components of physiological regulatory processes.

The [KIL-d] prion-like element in yeast epigenetically regulates viral gene expression

In the yeast Saccharomyces cerevisiae, the cytoplasmically-inherited double-stranded (ds) RNA killer virus confers on infected cells the phenotypes of toxin production and toxin resistance. These readily assayed phenotypes, which result from expression of the viral M dsRNA segment, facilitate assessment of viral gene expression in infected cells. In virus-infected cells, the prion-like [KIL-d] cytoplasmic genetic element places the viral dsRNA under epigenetic control by host cell regulatory elements. Strains harboring [KIL-d] can be cured of various cytoplasmic genetic elements without loss of [KIL-d], proving that [KIL-d] does not map on viral M or L-A dsRNA, the mitochondrial DNA genome, or the 2-micron DNA plasmid. In haploid cells harboring [KIL-d] and viral dsRNA, mitotically stable defective expression of toxin and/or resistance is observed. Upon mating the defective phenotypes are healed, so diploids are wild-type in phenotype. Upon meiotic sporulation, each haploid meiotic clone displays a variegated, but mitotically stable defect in killing and/or resistance, demonstrating that meiosis Aresets@ the epigenetic regulation. Cytoduction experiments prove that the nuclear fusion of mating is required for healing, i.e., wild-type strains receiving [KIL-d] do not show its phenotypic effect until after a cycle of mating and meiosis. This and other genetic experiments indicate that mating triggers healing and meiosis triggers phenotypic resetting in the presence of [KIL-d], independent of cell mating type or ploidy. In collaboration with Dr. Abram Gabriel (Rutgers University) we are studying how these nuclear events are sensed by the prion-like element. Furthermore, the effect of [KIL-d] is specific for the viral genome, since it alters expression of M dsRNA but not of cDNA derived from it when both are present in the same cells. This fact makes [KIL-d] a potential model for studying the interactions of prions and viruses.

[KIL-d] shows prion-like properties on reversion studies. The defective killer virus

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phenotypes of [KIL-d] haploids harboring M dsRNA revert to the wild-type phenotype with a relatively high frequency of 10-5. These wild-type revertants Aback revert@ to yield variegated defective phenotypes with a frequency of 10-3. This very high rate of back reversion to variegated phenotypes is not seen after the loss or mutagenesis of any known plasmid, but is similar to the variegated reappearance of the [PSI+] prion after it is lost. Thus, the cytoplasmically-inherited [KIL-d] element has prion-like genetic properties, although the cellular gene encoding the putative prion protein has not yet been identified. We have found that, like the [PSI+] prion, [KIL-d] can be transmitted from cell to cell by a protein extract. We plan to purify the transmissible principle, prove that it is a protein and determine the gene encoding it. Structure of yeast prions Previously at least two structural models have been proposed for the prions of yeast, in which hollow fibrils are made of stacked β-sheets arranged in various helical conformations. In collaboration with Dr. William Welsh (Cell & Molecular Pharmacology) we are testing the stability of these models in silico, in preparation for testing their predictions by means of site-directed mutagenesis. Beta-sheet blockers as therapeutic agents In collaboration with Dr. Stanley Stein, we have shown that peptidomimetic agents structurally related to the nucleation site of human A-beta(1-42) amyloid monomer peptide can specifically bind to the monomer and prevent the formation of amyloid in vitro. With Dr. William Welsh we plan to use these and other agents interacting with various amyloids to determine if we can develop bioinformatic approaches which will identify agents binding to proteins that are capable of forming amyloids; these agents might be useful to stain amyloids or to inhibit or reverse their formation, with potential application to the diagnosis and treatment of human amyloid diseases. Polymeric Bioconjugates for Drug Delivery In collaboration with Drs. Stanley Stein and Patrick Sinko (Rutgers University), we are studying the use of polymeric bioconjugate drug delivery methods to improve the bioefficacy of treatment of AIDS and cancer. The basis for much of this work is the use of conjugates in which various drugs are linked to poly(ethylene) glycol (PEG), resulting in reduced hydrolysis and renal clearance of the drugs and increased half-life. In addition, PEG conjugates decorated with multimeric effector molecules including cell targeting agents, membrane penetration agents and drugs are being developed. Multiple ligands for one or multiple cell surface receptors are being tested as means to delivering these conjugates to specific cells. We have shown that multiple copies of the chemoattractant peptide fMLF result in targeting of macrophages; experiments are planned to determine if the macrophage-specific mannose ligand shows similar effects of multiple copies on a single conjugate, and whether the two ligands might show synergistic targeting effects.

Highlights of the Year [KIL-d] is a cytoplasmically-inherited element in yeast which epigenetically regulates

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expression of the M double-stranded (ds) RNA genomic segment of the cytoplasmic killer virus. We have previously shown that [KIL-d] does not localize on the M or L-A viral dsRNA segments, mitochondrial DNA or 2-micron DNA. Although [KIL-d] has many properties of prions of yeast, until now its molecular nature has not been elucidated. We have recently shown that [KIL-d] can be transmitted from strain to strain by a protein extract, using a method that also transmits other yeast prions; this method fails to transmit killer virus. Studies are underway to identify the molecular nature of the transmissible principle carrying [KIL-d], with the goal of identifying the protein and the gene encoding it. Since the epigenetic effect of [KIL-d] regulates expression of the RNA viral genome but not of a cDNA derived from it, this may represent an exciting model system for studying the interactions of prions and viruses in eukaryotic cells. Publications Gunaseelan, S., Debrah, O., Wan, L., Leibowitz, M.J., Rabson, A.B., Stein, S., and

Sinko, P.J. Synthesis of poly(ethylene glycol)-based saquinavir prodrug conjugates and assessment of release and anti-HIV-1 bioactivity using a novel protease inhibition assay. Bioconjug Chem., 15:1322-1333. (2004).

July 27-August 1, 2004, Yeast Genetics and Molecular Biology Meeting, Seattle, WA.

R.B. Prasad and M.J. Leibowitz attended and presented poster and talk at Epigenetics Workshop: Prasad, R., and Leibowitz, M.J., Meiotic resetting of the [KIL-d] phenotype requires prior mating, regardless of ploidy, Abstracts, p. 196.

April 7, 2005, Stuart D. Cook, M.D., Master Educators’ Guild, Spring Symposium,

Piscataway, Poster Presentation: Erenrich, E.S., Langer, J.A., Anthony, L.J., Johnson, J., and Leibowitz, M.J. Extending the scope of a summer undergraduate research program through collaborations.

Presentations July 21, 2004, “Choosing and Applying to Graduate School,” RISE (Research in Science

and Engineering) at Rutgers/UMDNJ summer undergraduate research program. July 27-August 1, 2004, Yeast Genetics and Molecular Biology Meeting, Seattle, WA.

R.B. Prasad and M.J. Leibowitz attended and presented poster and talk at Epigenetics Workshop: Prasad, R., and Leibowitz, M.J., Meiotic resetting of the [KIL-d] phenotype requires prior mating, regardless of ploidy, Abstracts, p. 196.

September 14, 2004, presented talk “[KIL-d]: A Prion-like Element Epigenetically

Regulating Viral Gene Expression in Yeast” and “Research/Graduate Opportunities at UMDNJ-RWJMS and Rutgers University,” University of Maryland, Eastern Shore, Princess Anne, MD

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November 5, 2004 – Invited Faculty Participant in Panel Discussion in the RWJMS Postdoctoral Fellow Seminar Series, “On Being a Boss”

January 20, 2005, presented talk “[KIL-d]: A Prion-like Element Epigenetically

Regulating Viral Gene Expression in Yeast,” Hunter College, CUNY, New York, NY

April 7, 2005, Stuart D. Cook, M.D., Master Educators’ Guild, Spring Symposium,

Piscataway, Poster Presentation: Erenrich, E.S., Langer, J.A., Anthony, L.J., Johnson, J., and Leibowitz, M.J. Extending the scope of a summer undergraduate research program through collaborations.

April 18, 2005, invited speaker, “[KIL-d]: A Yeast Model for Prion-Virus Interactions,”

Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, China

April 20, 2005, invited speaker, “[KIL-d]: A Yeast Model for Prion-Virus Interactions,”

College of Life Sciences, Wuhan University, Wuhan China

June 16, 2005 – “A transfectable prion-like viral regulator in yeast,” invited graduate seminar, Medical Sciences Campus, University of Puerto Rico, San Juan, PR

June 29, 2005 - “Choosing and Applying to Graduate School,” RISE (Research in

Science and Engineering) at Rutgers/UMDNJ summer undergraduate research program.

Teaching RWJMS MGMB-6000/GSBS MICR-6000 14:125:402 Senior Design II, Department of Biomedical Engineering GSBS/RU DST-5000/16:115:556 Ethical Conduct of Research Laboratory Rotation in Microbiology & Molecular Genetics; RU 16:681:612. Laboratory Rotation in Molecular Genetics, Microbiology & Immunology, Rotation

Supervisor and Director of Bridge Program; GSBS MICR-5021. RISE (Research in Science and Engineering) Program (Summers 2004 and 2005) and Summer Neuroscience Research Program, Lecturer, Summer 2004 Seminars Sponsored January 13, 2004; Amar J. S. Klar, Ph.D., Section Head, Gene Regulation and

Chromosome Biology Laboratory, National Cancer Institute at Frederick; “Genetics of human hand-use preference, schizophrenia and bipolar traits” Department of Molecular Genetics, Microbiology and Immunology Seminar Series 2003-2004.

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Graduate Student Committee Memberships Jin Hyung Lee (Ph.D. Thesis Defense, 1/14/05) Kristi L. Muldoon (Cell Biology & Molecular Genetics, U of Maryland) Ramón Scharbaai Vazquez (U. of Puerto Rico, Medical Science Campus, Ph.D.

Proposal, 1/27/04) Helen Usansky (Pharmaceutical Sciences, RU, Ph.D. Proposal 11/10/03) Zhihong Yang (Ph.D. Proposal 12/12/03) Qidong Zhang (Proposal Examination July 20, 2004) Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Postdoctoral Fellows: Raj Prasad, Ph.D. Research Staff: Xiangyang Li, Research Specialist Muhammad Baig, Student Assistant Graduate Students Brian Gelfand, Research Rotation. Hector Diaz, Research Rotation Undergraduate Students Supervised: Nicole Torres, University of Puerto Rico-Humacao Campus, RISE at Rutgers/UMDNJ

Program. Olisumidele T. Akinsiku, Howard University, RISE at Rutgers/UMDNJ Program. Chelsie Swepson, Fayetteville State University, RISE at Rutgers/UMDNJ Program. Sana Shaikh, Rutgers College. Odette Williams, Livingston College, Rutgers University Ralitza Varlakova, Rutgers College Andrei Nesterov, Rutgers College. Administrative Committees Departmental - MGMI Equipment Committee Executive Committee Admissions Committee RWJMS Executive Council, non-voting member Administrative Team Member, Faculty Affairs Advisory Council

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University Associate Dean, UMDNJ-Graduate School of Biomedical Sciences, Piscataway Chairman, Executive Council, GSBS/Piscataway Director, Core Curriculum in Molecular and Cell Biology, UMDNJ-Rutgers University Director, M.D./Ph.D. Program, UMDNJ-RWJMS, with UMDNJ-GSBS, Rutgers

University and Princeton University Admissions/Advisement Committee, M.D./Ph.D. Program, UMDNJ-RWJMS Executive Committee, Rutgers University/UMDNJ Consolidated Programs in the

Molecular Biosciences Director, UMDNJ-Rutgers University Pipeline Program, NIH Initiative for

Maximizing Student Diversity Award Director, UMDNJ-University of Puerto Rico (Mayagüez Campus) Bridge to the

Doctoral Degree Program (NIH funded) Director, UMDNJ Component, Montclair State University-UMDNJ Bridge to the

Doctoral Degree Program (NIH funded) Director, Internal Bridge Program, Articulated M.S./Ph.D. Program Member, Cancer Institute of New Jersey and Scientific Advisory Council and Internal

Advisory Council of CINJ Admissions Committee, Biotechnology Training Program (joint with Rutgers, NIH) Internal Advisory Committee, UMDNJ-RWJMS Gerontological Institute Breast Cancer Research Program, CINJ Graduate Research And Education Training (GREAT) Group, AAMC, UMDNJ-RWJMS

Representative Co-Director, Molecular BioSciences Graduate Programs, Rutgers University and

UMDNJ-GSBS UMDNJ Representative, Northeast Alliance for Graduate Education and the

Professoriate, (NSF funded) Member, Health Disparities Focus Group, CINJ Member, Council of Graduate Schools Member, Society for the Advancement of Chicanos and Native Americans in

Science Member, Piscataway Summer Program Directors Member, Subcommittee on Institutional Planning, Assessment and Resource Allocation,

Middle States Accreditation Self-Study Member, Advisory Committee for the UMDNJ Presidential Search. (July, 2004) Member, MBRS and Bridges Program Directors Organizations

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Editing/Consulting Scientific Advisory Council, American Foundation for AIDS Research Consultant, University of Puerto Rico – Medical Sciences Campus, San Juan, Dr. Luis

Torres-Bauza (NIH funded) Reviewer for: National Science Foundation European Journal of Pharmaceutical Sciences

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Honghua Li, Ph.D. Research Activities Extending the Application of Our High-throughput Genotyping System. Realizing the advantages of a high-throughput approach in order to achieve a comprehensive understanding of biological systems, Dr. Li has put considerable effort on establishing a high-throughput genotyping system.. With this system, over 1000 SNPs can be analyzed in a single assay, with a sensitivity that allows the use of single haploid cells as starting material. Dr. Li first applied this system to the analysis of Single Nucleotide Polymorphisms (SNPs) on a large scale. During the past year, he has also used it successfully for gene expression profiling. More importantly, it was shown that the high-throughput system can be used to study gene expression in a quantitative way. A number of bioinformatic tools have been developed for analyzing data from the high-throughput assays. Understanding the Genetic Structure of the Human Genome. Meiotic recombination in humans has received considerable attention recently for its role in understanding the structures of the human genome and human evolution. Meiotic recombination is also likely to be one of the primary mechanisms for the formation of haplotype blocks, which are important for mapping genes responsible for complex diseases. However, very little is known about the detailed content of meiotic recombination and the mechanisms involved. Recent advances have allowed major progress in revealing details about the meiotic recombination process. However, study of this process still largely remains descriptive. Dr. Li’s success with developing a high-throughput multiplex genotyping system has enabled him to determine the genotypes of single sperm cells at a large number of genetic marker loci, and thus to study a chromosomal region in a great detail and to reveal the distribution of meiotic recombination along the length of chromosomes. The data obtained allowed Dr. Li to make significant progress in understanding the correlation between meiotic recombination and haplotype block formation and to understand the mechanisms underlying genetic recombination in a comprehensive way. Dr. Li has shown a strong correlation between meiotic crossovers and haplotype structure in a 2.5-Mb region on the long arm of chromosome 21. To investigate the role of meiotic recombination on haplotype block formation, SNPs were selected at a high density from a 2.5-Mb region of human chromosome 21. Direct analysis of meiotic recombination by high-throughput multiplex genotyping of 662 single sperm identified 41 recombinants. The crossovers were nonrandomly distributed within 16 small areas. All, except one, of these crossovers fall in areas where the haplotype structure exhibits breakdown, displaying a strong statistically positive association between crossovers and haplotype block breaks. The data also indicate a particular clustered distribution of recombination hotspots within the region. This finding supports the hypothesis that meiotic recombination makes a primary contribution to haplotype block formation in the human genome.

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Understanding the Genetic Basis of Breast Cancer on a Genomic Scale. Breast cancer presents as a spectrum of neoplastic growth. Clinically, various forms of proliferative lesions and malignancy have been observed. Although extensive histological and cytological variation has been documented, the molecular mechanisms underlying the high degree of heterogeneity of breast cancer remain poorly understood. It is widely believed that breast cancer development is a multi-step process caused by genetic alterations in a number of tumor suppressor genes and protooncogenes. We hypothesize that the high degree of heterogeneity of breast cancer is a reflection of involvement of different molecular pathways. On the other hand, differences in morphology may reflect alterations in distinct molecular pathways and may be used for understanding the genetic basis of breast cancer. To test the above hypothesis, Dr. Li has taken advantage of the fact that loss of heterozygosity (LOH) is usually associated with cancer development and has been shown to be an indication of tumor suppressor inactivation or protooncogene amplification. In most cases, LOH affects relatively large chromosomal regions containing the affected genes. Therefore, LOH can be detected by using genetic markers in these regions, even though these markers may not be necessarily located within the affected genes. By testing for LOH, the correlation between certain genes and the corresponding proliferative lesions can be studied even without knowing the genes and their protein products. Dr. Li has shown that over 1,000 SNPs in a single diploid cell can be detected robustly by a single assay and that a few hundred cells microdissected from breast tumor tissue sections can be used for LOH analysis. Data obtained in this way will allow Dr. Li to understand the molecular pathways underlying breast cancer development in a comprehensive way. It is expected that genome-scale analysis of breast cancer lesions and malignancy will generate a tremendous amount of new information. That may lead to new discoveries about the genetic basis of breast cancer. Understanding the Mechanisms Underlying Human Immunoglobulin VH Gene Complex Diversification. Human immunoglobulin VH gene segments are found on three chromosomes, i.e., 14q32, 15q11 and 16p11. Only the segments on chromosome 14 are shown to be expressed. The VH region on chromosome 14q32 contains 120-130 gene segments that are subdivided into seven families (VH1- VH7) based on the degree of sequence identity. Gene segments in each family share >80% identity. The VH region is highly diversified in gene segment number and composition. It is believed that the VH gene segments in any two individuals in the human population may have certain differences. The VH gene segments and their composition may also vary significantly between the carrying chromosomes (haplotypes). Previous studies by Dr. Li indicated that the VH region is diversified at the nucleotide sequence and gene segment levels. His very recent study by using newly developed technologies revealed even more variation in the VH region. One of the major genetic polymorphisms in the VH region is insertion/deletion (indel). However, detection of indel polymorphisms is limited by available techniques. Direct polymerase chain reaction (PCR) detection of polymorphisms requires sample homozygosity for one of the two alleles. For autosomal indel polymorphisms with their deletion alleles at a relatively low

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frequency, direct PCR detection becomes difficult or impossible. Dr. Li showed for the first time that indel polymorphisms could be detected directly in a human autosomal region, the immunoglobulin VH region, by using single haploid sperm cells as objects of study. In the initial study, unique marker sequences (n = 32), spaced at 5-kb intervals, were selected near the 3’ end of the VH region. Presence/absence of the markers were detected by amplifying these sequences from single sperm samples with multiplex PCR. After analyzing nine unrelated healthy donors (18 chromosomes), it was found that seven clustered markers in 6 of the 18 haplotypes were missing and likely represented a 35-40 kb indel polymorphism. The genotypes of the donors, with respect to this polymorphism, perfectly matched the expectation under Hardy-Weinberg equilibrium. Three VH gene segments, of which two are functional, are affected by this polymorphism. According to these results, >10% of individuals in the human population may not have these gene segments in their genome, and ~44% may have only one copy of these gene segments. The biological impact of this polymorphism would be very interesting to study. In a very recent study, the organization of the IGHV genes (n=108) on single human chromosomes was determined by detecting these sequences in single sperm using multiplex PCR amplification followed by microarray detection. A total of 374 single sperm samples from five Caucasian males were studied. Three deletion/insertion polymorphisms (Del I–Del III) with deletion allele frequencies ranging from 0.1 to 0.3 were identified. Del I is a previously reported polymorphism affecting three IGHV genes (IGHV1–8, IGHV3–9, and IGHV2–10). Del II affects a region 2–18 kb containing two pseudogenes IGHV(II)-28.1 and IGHV3–29, and Del III spans B21–53 kb involving genes IGHV4–39, IGHV7–40, IGHV(II)-40-1, and IGHV3–41. Deletion alleles of both Dels II and III were found in a heterozygous state, and therefore, could not be easily detected if haploid samples were not used in the study. Results of the present study indicate that deletions/insertions together with other possible chromosomal rearrangements may play an important role in forming the genetic structure of the IGHV region, and may significantly contribute to antibody diversity. Since these three polymorphisms are located within or next to the 3’ half of the IGHV region, they may have an important role in the expressed IGHV gene repertoire during immune response. Highlights of the Year During the academic year of 2004-2005, Dr. Li made significant progress toward accomplishing his research goals. He has further extended the application of high-throughput nucleic acid detection system for SNPs. This system has been used for studying meiotic recombination in great detail and on a large scale. He has also used it for studying genetic variation in breast cancer tissues and cell lines, and in colon cancer. Dr. Li has been very successful in using this marker system, for the first time, to detect meiotic recombination along entire chromosomes, to locate meiotic crossover points, and thus to improve the understanding of the mechanisms underlying meiotic recombination. Dr. Li has also made significant progress in understanding the genetic structure of the human immunoglobulin VH region. This finding may have significant impact on understanding the contribution of genetic structure of the VH region to the

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function of the immune system. Publications Wang H-Y, Luo M, Tereshchenko IV, Frikker DM, Cui X, Li JY, Hu G, Chu Y, Azaro MA,

Lin Y, Shen L, Yang Q, Kambouris ME, Gao R, Shih W, Li H. A Genotyping System Capable of Simultaneously Analyzing >1,000 Single Nucleotide Polymorphisms in a Haploid Genome. Genome Research, (2005)15:276-283.

Chimge, N.-O., Pramanik, S., Hu, G., Lin, Y., Gao, R., Shen, L., and Li, H. Three

insertion/deletion polymorphisms detected in the human IGHV region by multiplex analysis with single spermatozoa. Nat. Genes Immunity, (2005) 6, 186–193.

Teaching MGMB 6000 Microbiology and Immunology Laboratory Staff Marco Azaro, Research and Teaching Specialist Fang Chen, Graduate Student Xiangfeng Cui, Research Associate Danielle Frikker, Graduate Student Richeng Gao, Research Associate Guohong Hu, Graduate Student Minjie Luo, Postdoctoral Fellow Chimgee Nyam-Osor, Research and Teaching Specialist Sreemata Pramanik, Research and Teaching Specialist Li Shen, Senior Laboratory Technician Irina Tereschenko, Postdoctoral Fellow Hui-Yun Wang, Adjunct Assistant Professor Qifeng Yang, Research and Teaching Specialist Gang Yue, Research and Teaching Specialist Editing/Consulting Population Genetic Analysis Program: Immunity to Vaccines/Infections National Institute

of Allergy and Infectious Disease

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Michael Newlon, Ph.D. Highlights of the Year Added case history discussions to the Medical Genetics Course, and created web-based review quizes for each lecture in the course. Continued to add review quizes and visual resources to the web site of the Microbiology/Immunology course. In collaboration with Drs. Will Zehring of the Biochemistry department and Frank Wilson of the Neuroscience and Cell Biology department, planned for the integration of the Medical Biochemistry, Histology and Cell Biology, and Medical Genetics courses. Teaching

Dept of MGMI: MGMB 6000 Microbiology and Immunology

Interdepartmental MDC 6020 Cellular and Genetic Mechanisms Capstone Presentations for M-1 students (no course number) SHRP: PHYA 1439 Microbiology and Immunology for Physician Assistants Administrative Committees RWJMS Curriculum Committee First-year Course Director=s Committee

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Stuart W. Peltz, Ph.D. Dr. Peltz began a leave of absence from the University in November 2004. The work in his laboratory is covered under Dr. Joseph Dougherty’s section.

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Sidney Pestka, M.D. Chairman Research Activities The study of interferons, their receptors and signal transduction has been a major focus of the laboratory for many years. Early research in this area by Dr. Pestka’s group has led to the isolation, purification and characterization of the interferons, and subsequently their cloning and expression in bacteria; and identification of their receptor complexes. Interferons developed in the laboratory are currently available as approved therapeutics in the United States and worldwide for the treatment of various malignancies, viral diseases and multiple sclerosis. During this academic year, members of the laboratory have continued their endeavors to understand the interferons and their mechanisms of action. These efforts have led to a number of new paths, discovery of new cytokines, and unexpected directions, that are described in this summary. This past year Dr. Pestka and his associates discovered a series of new cytokines and cytokine receptors, including many novel interferons in many species. Of especial importance is the discovery of a new class of human interferon he named IFN-ν. Evolution of the Class 2 Cytokines and Receptors, and Discovery of New Friends and Relatives. Recombinant interferon-alpha (IFN-alpha) was approved by regulatory agencies in many countries in 1986. As the first biotherapeutic approved, IFN-alpha paved the way for the development of many other cytokines and growth factors. Nevertheless, understanding the functions of the multitude of human IFNs and IFN-like cytokines has just touched the surface. Up to the current time the known IFNs and IFN-like cytokines are IFN-alpha, IFN-beta, IFN-epsilon, IFN-kappa, IFN-omega, IFN-delta, IFN-tau, IFN-gamma, limitin, interleukin-28A (IL-28A), IL-28B, and IL-29. Much is also known about their receptors and signal transduction pathways. Analysis of the evolution of these molecules has provided some new insights into the development of these proteins as major elements of innate immunity. The sequencing of a wide variety of genomes and their transcripts has allowed researchers to determine how proteins or protein families evolved and how strongly during evolution a protein has been conserved. This past year Dr. Pestka analyzed the evolution of the Class 2 ligands and their cognate receptors by analyzing Class 2 ligand and receptor chain gene sequences from a variety of DNA sequence databases (Krause and Pestka, Pharmacol Ther. 106, 299-346, 2005). Both the Class 2 cytokines and receptor chains appear to have developed during the evolution of the chordate phyla: distant homologues of type I interferon (IFN) receptors are the only Class 2 cytokine receptors identified in the Ciona (sea squirt) genomes, while a wide variety of Class 2 ligands and receptor chains are encoded in the currently available genomes of bony vertebrates (teleost fish, amphibians, reptiles, birds, mammals). Phylogenetic trees of ligands and ligand-binding receptor chains demonstrated that proteins involved

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in conferring antiviral activity diverged before those involved in adaptive immunity. Genes encoding IFNs and IFN receptors duplicated multiple times during chordate evolution, suggesting that duplication of genes encoding IFN activity conveyed an evolutionary advantage. Altogether, these data support a model whereby the original Class 2 cytokines and receptors evolved and duplicated during the evolution of the chordate innate immune response system; new receptor and ligand duplications evolved into signaling molecules to fulfill communication requirements of a highly specialized and differentiated vertebrate immune system. In addition, the genomic analysis led to the discovery of some new members of this family of cytokines. Our phylogenetic analysis suggests that the IL-10-like ligands evolved from an IFN-like ligand; likewise the receptors binding IL-10-like ligands evolved from IFN receptors (Krause and Pestka, Pharmacol Ther. 106, 299-346, 2005). The Class 2 cytokine receptor family appears to have developed in chordate lineages to facilitate eradication of viral infections by restricting the spread of viral infection. We have identified IL-20R2 receptor homologs in several piscine genomes - not previously identified in fish. Moreover, we identified a family of IFN-δ proteins in the pig genome and delineated an evolutionary and structural link between murine limitin and pig IFN-δ. The analysis also permitted us to identify chicken and frog homologs of most mammalian Class 2 cytokine receptors and ligands as well as single ligand-binding receptor and accessory chains in urochordate genomes. In addition, the analyses enabled us to identify three new type I IFN families: IFN-αω, chicken IFN III and IFN-ν. IFN-αω proteins resemble evolutionary predecessors to IFN-α, IFN-ω and IFN-τ. Chicken IFN III is an avian type I IFN subtype that closely resembles mammalian type I IFNs. IFN-ν proteins appear to be obsolete IFN variants that have persisted as pseudogenes in primate lineages for about 40 million years. Since these IFN-ν pseudogenes have persisted virtually intact during this long period, they may have unique and novel functions to be discovered. This work was carried out by Christopher Krause. Continuing Discovery of New Protein Methyltransferases and Their Activities. In the past years Dr. Pestka’s group described the discovery of protein arginine methyltransferase 5 (PRMT5). During this year they found that Spliceosome Sm proteins D1, D3, and B/B' are asymmetrically dimethylated at arginine residues in the nucleus. Specifically they discovered a novel modification of spliceosome proteins Sm D1, Sm D3, and Sm B/B'. L292 mouse fibroblasts were labeled in vivo with [3H]methionine. Sm D1, Sm D3, and Sm B/B' were purified from either nuclear extracts, cytosolic extracts or a cytosolic 6S complex by immunoprecipitation of the Sm protein-containing complexes and then separation by electrophoresis on a polyacrylamide gel containing urea. The isolated Sm D1, Sm D3 or Sm B/B' proteins were hydrolyzed to amino acids and the products were analyzed by high-resolution cation exchange chromatography. Sm D1, Sm D3, and Sm B/B' isolated from nuclear fractions were all found to contain omega-NG-monomethylarginine and symmetric omega-NG,NG'-dimethylarginine, modifications that have been previously described. In addition, Sm D1, Sm D3, and Sm B/B' were also found to contain asymmetric omega-NG,NG-

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dimethylarginine in these nuclear fractions. Analysis of Sm B/B' from cytosolic fractions and Sm B/B' and Sm D1 from cytosolic 6S complexes showed only the presence of omega-NG-monomethylarginine and symmetric omega-NG,NG'-dimethylarginine. These results indicate that Sm D1, Sm D3, and Sm B/B' are asymmetrically dimethylated and that these modified proteins are located in the nucleus. In reactions in which Sm D1 or Sm D3 was methylated in vitro with a hemagglutinin-tagged PRMT5 purified from HeLa cells, Dr. Pestka detected both symmetric omega-NG,NG'-dimethylarginine and asymmetric omega-NG,NG-dimethylarginine when reactions were done in a Tris/HCl buffer, but only detected symmetric omega-NG,NG'-dimethylarginine when a sodium phosphate buffer was used. These results suggest that the activity responsible for the formation of asymmetric dimethylated arginine residues in Sm proteins is either PRMT5 or a protein associated with it in the immunoprecipitated complex. This effort was carried out in collaboration with Steven Clarke (UCLA) and Samuel Gunderson (Rutgers University). Members of the laboratory participating in this effort were Jin-Hyung Lee and Jeffry Cook. PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. This year Dr. Pestka’s group discovered a second protein arginine methyltransferase that synthesizes dimethylarginine. The cDNA for PRMT7, a recently discovered human protein-arginine methyltransferase (PRMT), was cloned and expressed in Escherichia coli and mammalian cells. Immunopurified PRMT7 actively methylated histones, myelin basic protein, a fragment of human fibrillarin (GAR) and spliceosomal protein SmB. Amino acid analysis showed that the modifications produced were predominantly monomethylarginine and symmetric dimethylarginine (SDMA). Examination of PRMT7 expressed in E. coli demonstrated that peptides corresponding to sequences contained in histone H4, myelin basic protein, and SmD3 were methylated. Furthermore, analysis of the methylated proteins showed that symmetric dimethylarginine and relatively small amounts of monomethylarginine and asymmetric dimethylarginine were produced. SDMA was also formed when a GRG tripeptide was methylated by PRMT7, indicating that a GRG motif is by itself sufficient for symmetric dimethylation to occur. Symmetric dimethylation is reduced dramatically compared with monomethylation as the concentration of the substrate is increased. The data demonstrate that PRMT7 (like PRMT5) is a Type II methyltransferase capable of producing SDMA modifications in proteins. This project was carried out in collaboration with Samuel Gunderson (Rutgers University), Arthur Felix (Ramapo College of New Jersey), and Ralf Hoffmann (University of Leipzig). The members of the laboratory performing this work were Jin-Hyung Lee, Jeffry Cook, Zhi-Hong Yang and Olga Mirochnitchenko. The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix and is dependent on N-linked glycosylation. This work was carried out in collaboration with Mark Walter (University of Alabama, Birmingham, Alabama). IL-22 is a class 2 alpha-helical cytokine involved in the generation of inflammatory responses. These activities require IL-22 to engage the

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cell surface receptors IL-22R1 and the low-affinity signaling molecule IL-10R2. IL-10R2 also interacts with five other class 2 cytokines: IL-10, IL-26, and the interferon-like cytokines IL-28A, IL-28B, and IL-29. In this study, Dr. Pestka defined the IL-10R2 binding site on IL-22 using surface plasmon resonance (SPR) and site-directed mutagenesis. Surprisingly, the binding hot spot on IL-22 includes asparagine 54 (N54), which is post-translationally modified by N-linked glycosylation. Further characterization of the glycosylation reveals that only a single fucosylated N-acetyl glucosamine on N54 is required for maximal IL-10R2 binding. Biological responses of IL-22 mutants measured in cell-based luciferase assays correlate with the in vitro SPR studies. Together, these data suggest that IL-22 activity may be modulated via changes in the glycosylation state of the ligand during inflammation. Members of the laboratory on this project were Lara Izotova and Barbara Schwartz. Design and construction of a phosphorylatable chimeric monoclonal antibody with a highly stable phosphate. Construction of phosphorylatable monoclonal antibodies (MAb) to Tumor Associated Antigens (TAA) has been a program for many years. The mouse monoclonal antibody B72.3 recognizes the tumor associated antigen TAG-72 that is expressed on the surface of human adenocarcinomas. This monoclonal antibody has begun to be used in clinical research protocols for the diagnosis and therapy of adenocarcinomas. To develop more effective methods for labeling this monoclonal antibody we introduced a phosphorylation site for the cAMP-dependent protein kinase (PKA) into chimeric monoclonal antibody B72.3 (MAb-chB72.3) by site-specific mutation of the coding sequence. The chimeric molecule contains the mouse variable region fused to the human IgG1 constant region. The phosphorylation site for PKA was positioned at the carboxyl terminus of the heavy chain constant region of the MAb chB72.3. The resultant modified MAb chB72.3-P was expressed in 293 cells and purified. The MAb-chB72.3-P protein was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase with [γ-32P]ATP to high radiospecific activity. The 32P-labeled MAb-chB72.3-P protein bound to cells expressing the TAG-72 antigen and was somewhat stable in serum, but not sufficiently stable to be used in human clinical trials. Although the introduction of phosphorylation sites into monoclonal antibodies (MAb) provides a novel procedure for labeling MAb for the diagnosis and treatment of cancers, more stable phosphates would be necessary. To prepare more stable phosphate linked to the Mab, we improved the procedure substantially. A recognition site for the cAMP-dependent protein kinase was introduced into the monoclonal antibody chCC49 (MAb-chCC49) by site-directed mutation of the coding sequence to make a variant of MAb-chCC49 containing a highly stable phosphate. To design this monoclonal antibody (MAb) without changing its immunoreactivity or biological properties, molecular modeling was used to locate appropriate regions for introduction of the cAMP-dependent phosphorylation site with desirable properties. We selected one position to mutate on the heavy chain based on molecular dynamics study of the solvated antibody. A vector expressing the mutant

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was constructed and transfected into mouse myeloma NS0 cells that expressed a high level of the resultant MAb-WW5. MAb-WW5 contained the cAMP-dependent phosphorylation site at the hinge region of the heavy chain, could be phosphorylated by the catalytic subunit of cAMP-dependent protein kinase with [γ-32P]ATP to high specific activity, and retained the phosphate stably. Compared with MAb-chCC49K1, another phosphorylatable variant of MAb-chCC49, the phosphate attached to MAb-WW5 showed much improved stability: about a 10-fold increase in resistance to hydrolysis. MAb-WW5 exhibited the same binding specificity to the TAG-72 antigen on MCF-7 4C10 breast cancer cells as we observed with MAb-chCC49K1. The improved stability of the attached phosphate provides a MAb with potential to be used in diagnosis and therapy of adenocarcinomas. Members of the laboratory involved in this effort were Wei Wu, Lara Izotova and Barbara Schwartz. This work was carried out in collaboration with John Kerrigan, Prem Yadav and Thomas Lavoie. Regulation of cytokine gene expression by mRNA turnover Cytokine expression by cells of the immune system plays a crucial role in the regulation of immune responses. Expression of many cytokines in response to external stimuli during an immune response is regulated by transcription as well as posttranscrptional events. A major posttranscriptional mechanism for regulating the level of gene expression of many cytokines, protooncogenes and growth factor mRNAs is through the control of mRNA turnover. The rapid turnover of mRNAs is determined in part by the A+U-rich elements in the 3'-untranslated region. The overall goal of this project is to understand the mechanisms of regulation of expression of cytokines involved in inflammation such as proinflammatory IFN-γ and anti-inflammatory IL-10. These cytokines have opposing effects and they antagonize each other’s production and functions. The details of this project are summarized by Dr. Srijata Sarkar under her section. Randi Foster contributed to this project. Publications Pestka, S., Krause, C. D., Sarkar, C., Walter, M. (2004) “Interferons,Interferon-like

Cytokines, and Their Receptors,” Immunological Reviews 202, 8-32 Miranda, T.B., Khusial, P., Cook, J.R., Lee, J-H., Gunderson, S.I., Pestka, S., Zieve,

G.W., and Clarke, S. (2004) “Spliceosome Sm proteins D1, D3, and B/B' are asymmetrically dimethylated at arginine residues in the nucleus,” Biochem Biophys Res Commun. 323, 382-387

Logsdon, N.J., Brandi, C., Jones, B.C., Allman, J.C., Izotova, L., Schwartz, B., Pestka, S., and Walter, M.R. (2004) “The IL-10R2 Binding Hot Spot on IL-22 is Located on the N-terminal Helix and is Dependent on N-linked Glycosylation,” Journal of Molecular Biology. 342, 503-514

Wu, W., Kerrigan, J.E., Yadav, P., Schwartz, B., Izotova, L., Lavoie, T.B., and Pestka, S. (2004) “Design and Construction of a Phosphorylatable Chimeric Monoclonal Antibody with a Highly Stable Phosphate,” Oncology Research/Incorporating Anti-Cancer Drug Design. 14, 541-558.

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Pestka, S., “Type I Interferons and Receptors,” in Topley & Wilson Microbiology and Microbial Infection - 10th Edition (M. Steward and S.H.E. Kaufmann, eds.), Arnold Publishers, London, England, 237-271.

Lee, J-H., Cook, J.R., Yang, Z-H., Mirochnitchenko, O., Gunderson, S., Felix, A.M., Herth, N., Hoffmann, R., Pestka, S. (2004) "PRMT7: A new protein arginine methyltransferase that synthesizes symmetric dimethylarginine," J Biol Chem. 280, 3656-3664.

Krause, C.D. and Pestka, S. (2005) “Evolution of the class 2 cytokines and receptors, and discovery of new friends and relatives,” Pharmacol. Ther. 106, 269-430.

Teaching Molecular Biology & Pharmaceutical Biotechnology - RutgersUniversity - S. Chen, Ph.D.

Course Coordinator - Development of Genetically Engineerd Pharmaceuticals: Interferon's discovery, Uses and Persepctives.

Medical Microbiology and Immunology - RWJMS/Piscataway - M. Newlon, Ph.D. Course Coordinator.

Current Concepts in Immunology, Robert Wood Johnson Medical School and Rutgers University – Yufang Shi, Ph.D., DVM, Course Coordinator.

Invited Speaker Special 21th Century Lecturer: “Seeing the Light: Stepping into Cells in Real Time,”

Kitasato Institute, Kitasato University, Tokyo, Japan, October 13, 2004. Invited speaker, “Seeing the Evolution of Interferons and Class 2 Cytokines and the

Origin of Innate Immunity,” 3M, St Paul, MN, May 18, 2005. Honors Warren Alpert Foundation Prize, Harvard University Graduate Student Committee Membership Zhihong Yang Laboratory Staff Jeffry Cook, Ph.D Adjunct Assistant Professor Srijata, Sarkar, Ph.D. Adjunct Assistant Professor Junxia Xie, Ph.D. Adjunct Assistant Professor Lara Izotova, Ph.D. Research Teaching Specialist II Barbara Schwartz, M.S. Research Teaching Specialist II Randi Foster Research Teaching Specialist III Olga Mirochnitchenko, M.S. Research Teaching Specialist IV Youngsun Kim, Ph.D. Research Teaching Specialist III Christopher Krause, Ph.D. Postdoctoral Appointee

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Natalia Zamolodchikov, Ph.D. Postdoctoral Appointee Jin-Hyung Lee Graduate Student Zhihong Yang Graduate Student Administrative Committees and Programs University Director, Graduate Program, Molecular Genetics and Microbiology, Graduate School of

Biomedical Sciences, UMDNJ-RWJMS Executive Council Clinical Research Center Advisory Board Scientific Council, Cancer Institute of New Jersey Executive Committee, Cancer Institute of New Jersey Internal Advisory Board, Cancer Institute of New Jersey Director, Cytokine, Growth Factors and Signal Transduction Program, Cancer Institute

of NJ Executive Committee, Consolidated Program in the Biomedical Sciences, Rutgers

University and Graduate School of Biomedical Sciences - UMDNJ at RWJMS Honorary Degree Award Committee Rutgers University Associate Director, Graduate Program in Microbiology and Molecular Genetics Community Involvement Member, North Caldwell Board of Health Member, Basic Pharmacology Advisory Committee of the Pharmaceutical

Manufacturers Association Foundation, Inc. Other Committe Memberships Secretary, International Society for Interferon and Cytokine Research Member, Columbia University Comprehensive Cancer Center, College of Physicians

and Surgeons, Columbia University International Advisory Committee of the Institute of Chemical Biology, Institute of

Molecular Biology and the Department of Chemistry, University of Hong Kong Editing/Consulting Editor, International Encyclopedia of Pharmacology and Therapeutics Editorial Board: Pharmacology and Therapeutics Journal of Interferon and Cytokine Research Anticancer Research Pharmaceutical Technology Cytokine and Growth Factor Reviews BioTechniques Journal of Biological Chemistry

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Associate Editor: Journal of Biological Regulators and Homeostatic Agents Oncology Research Molecular and Cellular Differentiation Editorial Academy

The International Journal of Oncology

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Arnold B. Rabson, M.D. Research Activities Dr. Rabson’s laboratory is continuing its research on the regulation of Human T-cell leukemia virus type 1 (HTLV-1) infection and on the roles of NF-κB and related proteins in human cancers. The laboratory has continued to study the mechanisms of latency and activation of integrated HTLV-1. The laboratory has identified the role of the T-cell activation pathway in activation of latent HTLV-1 demonstrating the roles of the T-cell receptor, the associated Lck kinase and the downstream Ras signal transduction molecule. Our studies suggest a model for activation of latent HTLV-1 in which T-cell receptor stimulation induces increased expression directed by the HTLV-1 long terminal repeat promoter, which in turn activates expression of the HTLV-1 Tax transactivation leading to a marked increase in HTLV-1 gene expression. Activation of the integrated HTLV-1 provirus may contribute to HTLV-1 pathogenesis through induction of expression of the HTLV-1 Tax gene from latently infected cells in vivo, leading to increased lymphoid proliferation. In collaboration with Dr. Yufang Shi, the laboratory is also studying the effects of HTLV-1 Tax on T-cell function in HTLV-1 Tax transgenic mice and attempting to use these mice to model HTLV-1 latency and pathogenesis. The laboratory is also studying the roles of HTLV-1 LTR promoter elements in viral infection through the use of a series of LTR mutations to dissect the roles of cellular and viral regulatory sequences in viral replication. Dr. Rabson’s laboratory is also continuing the study of mutations in the NF-κB pathways in human cancers. Previous studies had identified mutations in the NF-κΒ-2 gene in human cutaneous T-cell lymphomas. Other mutations truncated the C-terminus of the p100 protein, an inhibitor of the alternative pathway of NF-κΒ activation. Rabson’s studies have suggested that this loss of inhibitory activity leads to constitutive NF-κΒ activity contributing to lymphoma development. Recent studies have suggested that the truncated NF-κΒ-2 precursor proteins may also have biological roles in inducing gene expression that may contribute to T-cell lymphomas. On-going studies are dissecting the roles of NF-κΒ-2 mutation in lymphomagenesis and are using Affymetrix RNA expression arrays to identify genes activated by NF-κB mutations in lymphoma cells. In related studies, the Bcl-3 protein (related to the IκB regulators of NF-κB) is regulated by tyrosine kinases involved in T- and B-cell malignancies, and may mediate the oncogenic effects of these kinases. Dr. Rabson’s laboratory has also continued a series of exciting and important collaborations with other RWJMS and Rutgers scientists, particularly through his activities with the Cancer Institute of New Jersey. Over the last year, he collaborated with Dr. White to identify a role for hypoxia in inducing genomic instability in cancer cells, dependent upon the loss of the apoptotic pathway. This suggests a novel and critically important mechanism that may drive tumor progression. He has collaborated with Dr. Xiao of Rutgers to study the mechanisms by which HTLV-1 induces the NF-κB pathway as part of its oncogenic activity. Other collaborative studies with Drs. Leibowitz, Stein and Sinko have studied the ability to deliver anti-HIV drugs through

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slow-release polymer delivery systems and studies with Dr. PIlch have studied inhibition of RNAse H activity as an anti-HIV therapeutic approach. Dr. Rabson has also continued collaborations with Dr. A. Conney (Rutgers) on the possible effects of phorbol esters in cancer therapy. Highlights of the Year Dr. Rabson’s laboratory has delineated a pathway for activation of latent HTLV-1 through T-cell receptor activation. This result provides a possible mechanism for the pathogenesis of HTLV-1-induced diseases, in particular, Adult T-cell leukemia (ATL). Rabson hypothesizes that T-cell activation may lead to induction of latent HTLV-1 leading to expression of the viral oncogene, Tax. Induction of Tax expression would then lead to T-cell proliferation ultimately contributing to the oligoclonal and monoclonal proliferation associated with progression of HTLV-1 leukemia. Dr. Rabson’s collaborations with Drs. Stein, Leibowitz, Sinko and Pilch suggest new therapeutic targets and drug delivery approaches for HIV infection. Publications

Nelson, D.A., Tan, T.-T., Rabson, A.B., Anderson, D, Degenhardt, K., and White, E. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes and Development, 18:2095-2107, 2004.

Li, T.K., Barbieri, C.M. Lin, H.C., Rabson, A.B., Yang, G., Fan, Y., Gaffney, B.L., Jones, R.A., Pilch, D.S. Drug targeting of HIV-1 RNA:DNA hybrid structures: Inhibition of reverse transcriptase-mediated Rnase H activity and viral replication. Biochemistry, 43:9732-9742, 2004.

Qu, J.Z., Qing, G., Rabson, A., and Xiao, G. Tax deregulation of NF-κB2 p100 processing involves both β-TrCP-dependent and –independent mechanisms. J. Biol. Chem. 279:44563-44572, 2004.

Gunaseelan, S., Debrah, O., Wan, L., Leibowitz, M.J., Rabson, A.B., Stein, S. and Sinko, P.J. Synthesis of polyethylene glycol-based saquinavir prodrug conjugates and assessment of release and anti-HIV-1 bioactivity using a novel protease inhibition assay. Bioconjug. Chem. 15:1322-1333, 2004.

Lin, H.-C., Hickey, M., Hsu, L., Medina, D., and Rabson, A.B. Activation of Human T-Cell Leukemia Virus Type 1 LTR and Cellular Promoters by T-Cell Receptor Signaling and HTLV-1 Tax Expression. Virology, 339:1-11, 2005.

Avila, G.E., Zheng, X., Cui, X.X., Ryan,A., Hansson, A, Suh, J., Rabson, A., Chang,R.L., Shih, W.J., Lin, Y., Crowell, P., Lu, YP., Lou,Y.R. and Conney, A.H. Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) alone or in combination with all-trans retinoic acid on the growth of cultured human pancreas cancer cells and pancreas tumor xenografts in immunodeficient mice. J. Pharmacology and Experimental Therapeutics. 315:170-187, 2005.

Rabson, A.B. and Weissman, D. From microarray to bedside: targeting NF-κB for

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therapy of lymphomas. Clinical Cancer Research, 2005; 11:2-5.

Zhao, Y., Ramakrishnan, A., Kim, K.-E., and Rabson, A.B. Regulation of Bcl-3 through interaction with the Lck tyrosine kinase Biochemical and Biophysical Research Communications, ( in press, 2005).

Presentations Co-Chair, Workshop on HTLV Virology, 12th International Conference on Human

Retrovirology Teaching UMDNJ-RWJMS Department of Microbiology and Molecular Genetics, Medical

Microbiology and Immunology Course (First Year Medical Students), MGMB 6000 (Rutgers # 16:680:544). Lecture on HIV/AIDS (2 hours).

UMDNJ-RWJMS Department of Pathology and Laboratory Medicine, Pathology and Laboratory Medicine Course (Second Year Medical Students), PATH 7000, Small Group Leader (Path Talk), (9 three hour sessions and 1 hour review lecture).

UMDNJ-RWJMS Department of Family Practice, Alternative and Complementary Medicine Course, Lecture on Ayurveda, Indian traditional/herbal medicine for Medical School, (one hour lecture).

UMDNJ "Topics in Molecular Medicine" seminar on molecular medicine (one hour) UMDNJ/Rutgers Graduate Program in Molecular Genetics, Microbiology, and

Immunology, Course in Principles of Immunology, lecture on T cell activation (2 hours)

Rutgers University Molecular Biology and Biochemistry Senior Undergraduate Seminar, Session on Research Opportunities for Physician-Scientists

CINJ Medical Oncology Fellows, Lectures in Molecular Oncology (2 lectures) Honors Co-Chair, Workshop on HTLV Virology, 12th International Conference on Human

Retrovirology Foundation of UMDNJ Award for Excellence in Teaching (Award for UMDNJ-Robert

Wood Johnson Medical School Teaching for 2005) Seminars Sponsored September, 2004, Dr. Patricia Dahia, Dana-Farber Cancer Center. CINJ Division of

Cancer Genomics and Molecular Oncology Seminar January, 2005, Dr. David Tuveson, Department of Medicine, University of

Pennsylvania. CINJ Grand Rounds. February, 2005, Dr. Yang Shi, Department of Pathology, Harvard Medical School, CINJ

Grand Rounds.

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March, 2005, Dr. Igor Jurisica, Toronto Cancer Center, University of Toronto, CINJ Division of Cancer Genomics and Molecular Oncology Seminar

March, 2005, Dr. Ronnie Drapkin, Dana-Farber Cancer Center, Harvard Medical School Department of Pathology, CINJ Division of Cancer Genomics and Molecular Oncology Seminar

June 2005, Dr. Eileen White, Rutgers University, CABM and CINJ, CINJ Distinguished Lecturer.

Graduate Student Committee Memberships Jihwan Hwang, UMDNJ- RWJMS Biochemistry Program, advisor, Dr. M. Inouye.

Defense 10/04 Yari Marin, Rutgers University Microbiology and Molecular Genetics, advisor, Dr. S.

Chen. Defense 6/05. Katie Doktor, Rutgers University Microbiology Program, advisor, Dr. A. Rabson, MS

Defense 8/04. Lynn Lagos, UMDNJ-RWJMS Molecular Genetics and Microbiology Program, advisor,

Dr. C. Gélinas. MS Defense 7/04. Gina Avila, Rutgers University, advisor, Dr. A. Conney, MS 7/04. Xi Wang, UMDNJ-RWJMS Molecular Genetics, Microbiology, and Immunology

Program, advisor, Dr. M. Shen Jui Dutta, UMDNJ-RWJMS Biochemistry Program, advisor, Dr. C. Gélinas. Matthew Simmons, UMDNJ-RWJMS Biochemistry Program, advisor, Dr. C. Gélinas.

Tin-Ting Tan, Rutgers University Molecular Biology and Biochemistry, advisor, Dr. E. White.

Alison Tuske, UMDNJ-RWJMS Molecular Genetics, Microbiology, and Immunology Program, advisor, Dr. A. Rabson.

Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Hsin-Ching Lin, Ph.D., Research and Teaching Specialist Peter Simon, Ph.D., Postdoctoral Fellow Alison Tuske, Graduate Student Katie Doktor, Medical Student Sara Akbari, Medical Student Lisa Stagmer, Undergraduate Student Administrative Committees UMDNJ-RWJMS Advisory Committee on Appointments and Promotions Core Facilities Subcommittee of the UMDNJ-RWJMS Research Committee Member, Search Committee, Vice-President for Research, UMDNJ UMDNJ-RWJMS Campus Presidential Candidate Interview Committee

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Departmental Department of Pathology, Search Committee. Rutgers Laboratory of Cancer Research, Search Committee Rutgers BIOMAPS, Member, Executive Committee, NIH Workforce Training Grant in

Integrated Proteomics EOHSI Pilot Project Grant Review Committee CABM CABM Symposium Organizing Committee

CINJ Associate Director for Basic Sciences, CINJ Leader, Program in Transcriptional Regulation and Oncogenesis, CINJ Director, CINJ Division of Cancer Genomics and Molecular Oncology Chairman, CINJ Collaborative Research Award Grant Review Committees Cancer Institute of New Jersey Scientific Council Cancer Institute of New Jersey Executive Committee Executive Committee, CINJ Training Program in Translational Cancer Research, Search Committee, CINJ Hematologic Malignancies Tumor Study Group Search Committee, CINJ Division of Medical Oncology Chairman, Search Committee, CINJ Division of Cancer Genomics and Molecular Oncology Member, Internal Advisory Board, Dean and Betty Gallo Prostate Cancer Center. CINJ Strategic Planning Advisory Committee Planning Committee, New Jersey Governor’s Conference on Effective Partnering in

Cancer Research CINJ Cancer Center Support Grant and Research Subcommittee Federal/State Appointments Federal NIH Oncologic Sciences Cancer Molecular Pathobiology Study Section, ad hoc Member, NIH Oncologic Sciences IRG, Special Emphasis Panels Reviewer, NCI Cancer Center Support Grant Site Visit team Editing/Consulting Senior Editor, Clinical Cancer Research Editorial Board, Journal of Biomedical Science Associate Editor, Cancer Research Reviewer for: Journal of Virology

Virology Cancer Letters

Journal of Clinical Investigation

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Yacov Ron, Ph.D. Research Activities

Prevention and treatment of EAE by the induction of clonal anergy to encephalitogenic determinants of myelin antigens.

Retroviral-mediated gene transfer technology is employed to express synthetic genes encoding the whole myelin basic protein (MBP), proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG) or minigenes encoding the encephalitogenic determinants of these proteins in normal antigen presenting B cells. These synthetic genes also encode lysosomal targeting sequences in order to facilitate association with MHC class II molecules. This approach is based on the findings that normal, resting B cells induce antigen-specific T cell unresponsiveness rather than activation. We have shown that B cells expressing a PLP-derived encephalitogenic determinant inhibit the ability to induce EAE in susceptible animals and completely block relapses in animals treated during the first remission period. We have also shown that treated animals were specifically tolerized (anergized) to the PLP determinant encoded by the synthetic gene. The same treatment was also efficacious in blocking spontaneous EAE induction as well as reversing ongoing disease in PLP-specific TCR transgenic animals which will all develop terminal disease if not treated.

Lymphoid and myelopoiesis and homeostasis. Using retroviral tagging, a myeloid precursor cell population that can give rise to the whole myeloid system was identified in the spleen. This cell population is non self-renewing, and will not reconstitute the BM of irradiated animals. It is, however, a very long-lived population and will reconstitute the myeloid system for at least 6 months. These findings contradict the common dogma according to which only pluripotential stem cells can replenish the entire hematopoietic system. Similarly, our studies on lymphopoiesis show that both B and T cells can develop independently from other hematopoietic lineages and that there is a lineage-specific homeostatic mechanism that engages the two lymphoid subpopulations. These studies are based on BM chimeras reconstituted with BM taken from mouse strains lacking one or more component of the lymphoid system which allows us to follow the appearance of host-derived lymphoid cells in the reconstituted mice. Publications Smith, K. M. Brewer, J., M. Mowat, A., MCI., Y. Ron, and P. Garside. 2004. The

influence of follicular migration on T cell differentiation. Immunology, 111:248.

Chen, C-C., A. Rivera, J. P. Dougherty, and Y. Ron. 2004. Complete protection from relapsing experimental autoimmune encephalomyelitis. Blood, 103:4616

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Teaching Medical Microbiology & Immunology Molecular Biology and Pharmaceutical Biotechnology Molecular Biology of Cells (16-148-514) Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Chiann-Chyi Chen Nomi Ron Ayelet Avni Administrative Committees RWJMS: Safety Committee

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Aaron J. Shatkin, Ph.D. Research Activities An important feature of gene expression in a broad range of eukaryotes from yeast to humans is the addition of a m7GpppN cap to nascent mRNA 5´ends. The cap structure marks transcription start sites and regulates mRNA stability, splicing, nuclear transport and translation initiation facilitated by cap binding proteins. Caps are synthesized by three enzymatic steps catalyzed sequentially by RNA triphosphatase (RT), guanylyltransferase (GT) and methyltransferase (MT). All three activities have been shown to be required for viability in yeast. Transcripts that are uncapped are rapidly degraded while RNAs containing unmethylated caps fail to direct protein synthesis. Dr. Shatkin has cloned, sequenced and characterized the human, mouse and worm capping enzymes. In contrast to separate enzymes in unicellular eukaryotes, metazoans contain a bifunctional capping enzyme (CE) consisting of N-terminal RT and C-terminal GT. CE selectively bound RNA polymerase II via interaction of the GT domain with the C-terminal heptad repeat sequences in the polymerase largest subunit. This association stimulated capping. CE binding also relieved repression by negative elongation factor in transcription complexes, suggesting that it plays a critical role in elongation checkpoint control during promoter clearance. These and other results point to a functional connection between capping and transcription. Additional protein-protein interactions, for example between MT and the nuclear transporter importin-α, imply linkage also between capping and protein transport. RNA interference (RNAi) knockdown of CE in C. elegans was embryonic lethal. Dr. Shatkin also showed that capping is also essential for viability in mammalian cells. Knockdown of CE in human cells by small interfering RNA (siRNA) resulted in apoptosis as measured by TUNEL assay and caspase-3 activation. siRNA knockdown of the cap MT also induced programmed cell death. Viability could be restored by transfection of truncated MT that retained a nuclear localization sequence (NLS) and associated with transcription complexes in the nucleus. By contrast, a truncated MT that was missing a NLS and thus localized to the cytoplasm, although catalytically active, failed to reverse the siRNA-induced apoptotic effects of MT knockdown. The results demonstrate that mRNA capping is a key component of the network of interacting pathways required for homeostasis in mammalian cells and eukaryotes generally.

Highlights of the Year Demonstrated that mRNA modification is essential in mammalian cells and disruption of any one of the three enzymatic activities responsible for mRNA 5’ capping induces programmed cell death.

Research Funding

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Source: NIH T32 GM 08339 Title: Rutgers-UMDNJ Training Grant in Biotechnology Period: 07/01/90-06/30/10 (renewal pending) Amount: $2,014,759 (annual direct costs)

Publications

Shafer, B., Chu, C., and Shatkin, A.J. (2005) Human mRNA Cap Methyltransferase: Alternative Nuclear Localization Signal Motifs Ensure Nuclear Localization Required for Viability. Mol. Cell. Biol. 25:2644-49.

Chu, C., Shafer, B. and Shatkin, A.J. (2005) Apoptosis Is Induced in Mammalian Cells by siRNA Knock-down of mRNA Capping Enzymes. Cold Spring Harbor Meeting on Eukaryotic mRNA Processing.

Shatkin, A.J. (2005) Gene Regulation: mRNA Capping. Henry Stewart Talks, London (on line).

Presentations Mandal, S.S., Chu, C., Wada, T., Handa, H. Shatkin, A.J. and Reinberg, D.: Co-

transcriptional Capping of mRNA and the Role of Capping Enzyme during Promoter Escape by RNA Polymerase II. Amer. Chem. Soc., Philadelphia, August 2004.

Teaching Advanced Biotechnology 155:604

Honors AAMC Award for Distinguished Research in the Biomedical Sciences

Seminars Sponsored 10/25/04, 18th Annual CABM Symposium, “Protein Structure & Human Disease” 11/10/04, Dr. Robert Darnell, Rockefeller University, “Tumor Immunity and Neuronal

Function: Insights from Paraneoplastic Neurologic Degeneration” 1/26/05, Dr. Gregory Hannon, Cold Spring Harbor Laboratories, “RNAi: Mechanism

and Application” 2/23/05, Dr. Barry Honig, Columbia University, “Combining Biophysics and

Bioinformatics to Predict Protein Structure and Function” 3/23/05, Dr. Matthew P. Scott, Stanford University, “Hedgehog Signaling in

Development and Disease” 4/6/05, Dr. Joan Brugge, Harvard Medical School, “Morphogenesis and

Oncogenesis in 3D Breast Epithelial Cultures” 4/11/05, Dr. Yasuhiro Furuichi, Genecare Research Institute Co., Japan, “Genes

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that Induce Apoptosis Selectively in Tumor Cells” 5/11/05, Dr. Christopher Walsh, Harvard Medical School, “Genes that Control the

Shape and Size of the Human Cerebral Cortex” 6/8/05, Dr. Clifford J. Tabin, Harvard Medical School, “Patterning the Vertebrate

Limb and Heart”

Graduate Student Committee Memberships Rushad Pavri, Biochemistry, Qualifying Exam Cuifeng Yin, Biochemistry & Mol. Biol., Thesis J.H. Lee, Biochemistry, Thesis Hudan Liu, Biochemistry, Thesis Rushad Pavri, Biochemistry, Thesis

Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Joseph Bauman Predoctoral student Chun Chu Predoctoral student

Administrative Committees Departmental: CABM Symposium CABM Lecture Series CABM Retreat NIH Biotech Training Program Retreat RWJMS Cancer Institute of New Jersey (CINJ) Internal Advisory Board Child Health Institute of New Jersey (CHINJ) Directorship Search (Co-Chair) Strategic Planning Committee CABM/Pharmacology Faculty Search Committee CABM/Biochemistry Faculty Search Committee University Central Committee on Restructuring Federal/State Appointments Rutgers Cook College/Nigeria Biotechnology National Biotechnology Center of Spain Scientific Advisory Board External Advisory Board (Chairman) Cleveland Clinic Research Institute H. Hughes Medical Institute Scientific Review Panel Ivy Charitable Foundation Board Salzman Virology Award Selection Committee Committee to Review NJ Life Sciences Research Proposals Community Involvement on Behalf of University or Medical School:

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Rutgers Research Advisory Board Rutgers Central Committee on Proposed Merger (Chairman) Waksman Institute Faculty A&P Committee Rutgers MBB Chairman Search Committee Rutgers Conflict Resolution Committee Rutgers Cook College Dean Search Committee Rutgers Centers of Excellence Sub-Committee

Editing/Consulting Editor: Advances in Virus Research

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Yufang Shi, D.V.M, Ph.D.

Research Activities Mechanisms of Apoptosis in T Helper Subsets

Investigating the molecular mechanisms that controls apoptosis in T cells has been one of the major interests of Dr. Shi’s laboratory. His recent efforts have been on elucidating the differences of the mechanisms that control apoptosis in Th1 and Th2 cells. He has shown that while Th1 cells die by the Fas-mediated caspase pathway, Th2 cells die through intracellularly activation of granzyme B. We also found that prostaglandin E2 (PGE2) specifically protected Th2 cells from AICD by downregulating granzyme B. Thus, differences in the expression of, and susceptibility to, death effectors are a built-in mechanism that controls the Th1-Th2 balance.

Regulation of RANKL expression in T cells The ligand for receptor-activator of NF-κB (RANKL) plays a critical role in the homeostasis of bone metabolism by regulating the function and viability of osteoclasts. We have shown that T cells also express RANKL and its expression is regulated by TCR ligation, which was further increased many-fold by low amount of PGE2. Dr. Shi’s recent data demonstrate that PGE2 delays the decay of TCR-induced RANKL mRNA. He is currently investigating how TCR and PGE2 control RANKL mRNA stability in the context of autoimmune arthritis pathogenesis.

Regulation of Immune Tolerance by Mesenchymal Stem Cells and Apoptotic Cells

Dr. Shi has shown that apoptotic cells can prevent heart transplant rejection. He is currently investigating the cellular mechanisms. He has recently established an in vivo system to investigate cell interactions during this tolerance induction process. In addition, he has also studied the role of apoptotic cells in the immune response to tumors and with the goal of determining the effect of apoptotic cells in tolerance induction in the tumor microenvironment. A new project recently initiated in Dr. Shi’s lab is to study the mechanisms of bone marrow derive mesenchymal stem cells in the regulation of immunosuppression. We have shown that mesenchymal stem cells have a dramatic effect on T cells activation and proliferation. We are investigating the cellular and molecular mechanisms that mediate such strong immunosuppressive effects by this specialized cell population.

Stress and the Immune System. Physical and psychological stressors have significant effects on the immune system. Our studies have shown that the reduction in lymphocyte numbers caused by chronic restraint in mice occurs through endogenous opioid-mediated Fas upregulation, which in turn mediates apoptosis. Dr. Shi has recently found similar results with the mouse hindlimb unloading model, an experimental system simulating some of the deleterious effects of spaceflight. Hindlimb suspension was found to drastically deplete various cell populations in the spleen and thymus. Surprisingly, administration of opioid antagonists or interference with the Fas-FasL interaction was able to block the reduction in

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splenocytes, but not thymocytes. On the other hand, steroid receptor antagonists blocked lymphocyte losses in both spleen and thymus. Therefore, the effects of hindlimb suspension on the homeostasis of splenocytes and thymocytes must be exerted through distinct mechanisms. To elucidate which cells are responsible for the induction of apoptosis during hindlimb suspension, Dr. Shi depleted CD4+CD25+ cells and found that this treatment could protect splenocytes. In addition, mice depleted of CD4+CD25+ cells are protected from the immunosuppression caused by hindlimb suspension. Highlights of the Year In the past year, Dr. Shi has made significant progress in several areas. He has made significant advancement in our understanding of the role of granzyme B in the regulation of Th2 apoptosis. Mice deficient in granzyme B develop more severe allergic asthma. He also made significant progress in the understanding of the mechanisms that regulate RANKL expression in T cells. His new in vivo system provided us with a unique opportunity to study how apoptotic cells regulate immune response. The establishment of the mesenchymal stem cell project gives Dr. Shi a unique niche to using his immunology expertise to investigate the mechanisms controlling mesenchymal stem cell-mediated immunosuppression; it is also hoped that his study will provide new information for proper clinical application of these cells. His project on the stress and radiation has been focused on the development of new countermeasures in response to the directional changes in NASA research. He has also shown that vitamin C can effectively protect mice thymocyte from stress induced reduction. We also found that CD4+CD25+ T regulatory cells play a key role in stress induced peripheral lymphocyte reduction. Publications Jin QH, He HY, Shi YF, Lu H, Zhang XJ . 2004 Overexpression of acetylcholinesterase

inhibited cell proliferation and promoted apoptosis in NRK cells. Acta Pharmacol Sin. 25(8):1013-21.

Sun, EW, LY Zhang, AI Roberts, C Liu and YF Shi. 2005. Chronic stress induced death of lymphocytes. Cytokines: Stress and Immunity, Second Edition, edited by Nicholas P. Plotnikoff, Robert E. Faith, Anthony J. Murgo, and Robert A. Good. CRC Press

Greeneltch, KM, Kelly-Welch AN, Keegan, A.D. and Shi, Y.F. 2004. Chronic Morphine Administration Promotes Th2 Differentiation via a Fas/FasL-Dependent Mechanism. J. Immunology, 175: 4999-5005.

Yuan, ZR, Wang, RX, Lou, XY, Zhang, LY and Shi, YF. 2005. Identification and Characterization of a Novel Cell Survival Gene Critical in Apoptosis and Tumorigenesis. Cancer Research, 65: 10716-24

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Presentations 2004. July, Prostaglandin E2 Enhances TCR Activation-Induced Expression by

Regulation of mRNA Decay, 12th International Congress of Immunology, Montreal

2004. July, Apoptosis Modulates the Th1/Th2 Balance: Distinct Roles for Caspases and Granzyme B 12th International Congress of Immunology, Montreal

2004, October, Apoptosis in the immune system. Symposium on human primate disease models Kuming, China

2004, October, apoptosis and disease. Taian Medical College, Taian, China. 2005, April, T cell apoptosis and immune regulation. Third Congress of the Federation

of Immunology Societies of Asia-Oceania. Hangzhou, China 2005, April, Chairman, Apoptosis Workshop, Third Congress of the Federation of

Immunology Societies of Asia-Oceania. Hangzhou, China Teaching Course Director, Micr 6005, Current Concepts in Immunology, Robert Wood Johnson

Medical School and Rutgers University (course number: 16:681:543) Lecture on “Immunodeficiency and Inflammation/Hypersensitivity” in the “Medical

Microbiology and Immunology (MGMB 6000)” course for medical students. Lecture on “Immunosuppression and Transplantation” Lehigh University Seminars Sponsored Patricia Morris, Professor, Rockefeller University: Cytokines regulate the StARs: a tale

of interleukins and START domain expression. January 18, 2005 Graduate Student Committee Memberships Division of Life Sciences, Rutgers University, Ph.D. Committee, Kristina, Liu, 2002-

Present Division of Life Sciences, Rutgers University, Ph.D. Committee, Sabarna Kahn, 2003-

2005 Division of Life Sciences, Rutgers University, Ph.D. Committee, Hema Tirumalai, 2003-

2006 UMDNJ-RWJMS, Ph.D. Committee, Na Li, 2003-Present UMDNJ-RWJMS, Ph.D. Candidacy Lin Zheng, 2003-Present UMDNJ-RWJMS, Ph.D. Committee, Matt Simmons 2004-2004 UMDNJ-RWJMS, Ph.D. Committee, Anna Knapinska, 2004-present UMDNJ-RWJMS, Ph.D. Committee, Tanishia Williams 2003-2004 UMDNJ-RWJMS, Ph.D. Committee, Youyi Peng 2003-2005 UMDNJ-RWJMS, Ph.D. Committee, Amit Balakrishnan 2003-present UMDNJ-RWJMS, Ph.D. Committee, Xin Li, 2003-present UMDNJ-RWJMS, Ph.D. Committee, Ting Wen 2004-present

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Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Laboratory Support Staff Cathy Liu, M.Sc. Liying Zhang, M.D. Arthur Roberts, M.Sc. Postdocs Satish Devadas, Ph.D. Jyoti Das, Ph.D. Zeng-Rong Yuan, M.D., Ph.D. Guangwu Xu Predocs Guangwen Ren, Alison Tiske (co-supervisor) Arthur Roberts (part-time) Yingyu Zhang Kathryn Wang (co-supervisor) Summer Students Rhea Chakraborty Marielly Cueras Visiting Scientists Erwei Sun Xue-Jun Zhang Junior Faculty Mentoring Robert Laumbach MD, MPH, CIH, Assistant Professor, Department of Environmental

and Community Medicine, EOHSI Administrative Committees Departmental Director of the Flow Cytometry Facility Director of the Real-Time PCR RWJMS Award Nomination committee MD/Ph.D. Recruitment committee Federal/State Appointments Member, Team of Infection, Immunology and Hematology, National Space Biomedical

Research Institute, NASA Community Involvement on Behalf of University or Medical School

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Grant review committees: Member, Department of Defense, Molecular Genetics Peer Review Panel of the

Congressionally Directed Medical Research Programs On Prostate Cancer Research

Member, Department of Defense, Molecular Biology Peer Review Panel of the Congressionally Directed Medical Research Programs On Breast Cancer Research

Member, Department of Defense, Congressionally Directed Medical Research Programs On Breast Cancer Research: Concept Award.

Member Department of Defense, Clinical Trial, Peer Review Panel of the Congressionally Directed Medical Research Programs On Breast Cancer Research

External reviewer, Research Grant Council, Hong Kong Government Philip Morris External Research Program The Florida Department of Health, Biomedical Research Program. United States-Israel Binational Science Foundation Program project Review: ZAG1 ZIJ-5, NIH Ad-hoc member, Cellular and Molecular Immunology Study Section A, NIH Ad-hoc member, Cellular and Molecular Immunology Study Section B, NIH 2005, New York Health Department, Breast Cancer Postdoctoral Fellowship Review

Panel Editing/Consulting Journal Editorial Boards Member of Editorial Board: Cellular and Molecular Immunology Editors Associate Editor-in chief: Cell Research Books Chapter 11: Chronic Stress Induces Death of Lymphocytes by E. Sun, L. Wei, A.

Roberts, C. Liu and Y. Shi in Cytokines Stress and Immunity, edited by Nicholas Plotnikoff.

Reviewer Journal of Immunology Molecular and Cell Biology Cell Death and Differentiation Proceedings of National Academy of Science Cancer Research Blood Brain Behavior and Immunity International Immunology Clinical Immunology and Immunopathology

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Cellular ImmunologyLife Sciences Journal of Biological Chemistry

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Victor Stollar, M.D. Vice Chairman Research Activities The work in Dr. Stollar’s laboratory centers on Sindbis virus (Family Togaviridae, genus alphavirus), a mosquito transmitted virus. Sindbis virus(SV) encodes 4 nonstructural proteins, which together form a complex, which is responsible for the replication and transcription of viral RNA. The central player in this complex is the nonstructural protein, nsP4 (610 amino acids), the viral RNA-dependent RNA polymerase (RDRP). In addition to the genomic RNA, a second mRNA is made in infected cells; this is a subgenomic (SG), and it serves as the message for the viral structural proteins. In last year’s report, Dr. Stollar described a mutant of Sindbis virus, SVPZF, which he isolated several years ago. SVPZF is resistant to pyrazofurin (PZF) a nucleoside analog which interferes with pyrimidine biosynthesis, and thus lowers the level of both UTP and CTP in treated cells. This mutant, in contrast to his standard virus, replicates well in cells treated with PZF. Furthermore, the yield of SVPZF from mosquito cells is increased from 20 to 50 fold in the presence of low levels of PZF, suggesting that this mutant actually replicates better in cells with low levels of UTP and CTP than in cells with normal levels of these rNTPs. This stimulatory effect of PZF on SVPZF is reversed by addition of uridine or cytidine to infected cells. Both of these nucleosides lead to an increase in the cellular levels of UTP and CTP. Thus, whereas PZF inhibits the replication of the standard Sindbis virus (SVSTD), it stimulates the replication of SVPZF; and independent of whether PZF inhibits or stimulates the replication of virus, the effect of PZF is reversed by uridine. Dr. Stollar also noted in last year’s report that SVPZF has a second phenotype, i.e. it makes decreased amounts of the SG RNA, a phenotype that is reversible by the addition of adenosine, which acts, he believes, by increasing the level of ATP. The first step in the synthesis of SG RNA is the binding of the transcriptase to the promoter for the synthesis of SG RNA. Accordingly, to investigate how the synthesis of SG RNA is regulated, he established a system to monitor the binding of the SV transcriptase to the SG promoter. To do this Dr. Stollar purchased a 24 mer oligoribonucleotide with a sequence corresponding to the minimal sequence that has SG promoter activity (SGprmtr.min); and as a source of the SV nonstructural proteins (nsPs), he used P15 fractions of BSC40 cells infected with recombinant vaccinia virions expressing various of the four SV nsPs. The SGprmtr.min was labeled with 32P at its 5' end and incubated with P15 fractions from BSC 40 cells expressing the different SV nsPs. Binding of the nsPs was detected by a gel mobility shift assay. Although, the nonstructural protein, nsP4, is the viral RDRP, nsP4 by itself did not bind to the SGprmtr.min. Only when all four of the nsPs were present was binding observed. This observation is in accord with the idea that the SV nsPs exist and function as a tightly knit multiprotein complex, a suggestion made by others on the basis of antibody

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pull down experiments. Making use of this binding system along with UV crosslinking experiments, Dr. Stollar conclusively identified nsP4 as the nsP that binds to the SG promoter, and he identified an amino acid sequence in nsP4 that is involved in this binding. This sequence is highly conserved among the alphaviruses. To further facilitate the study of how the synthesis of SG RNA is regulated, Dr. Stollar recently established a cell-free system to make SG RNA. This is the first such system described for any alphavirus. The two critical elements of this system are (1) a promoter-template RNA which contains the minus-strand SV RNA sequence corresponding to positions -157 to +175, where the initiating nt for SG RNA synthesis is +1. (2) A p15 fraction similar to that used in the binding assays. This system is now being optimized. All of this work was done together with Dr. Mei-Ling Li Highlights of the Year The development of a system for assaying the binding of the SV transcriptase to the SG promoter. Experiments with this system showed that the viral RDRP (nsP4), by itself did not bind to the promoter; for binding to occur all four of the nonstructural proteins had to be present. Additionally, an amino acid sequence was identified in nsP4 that was directly involved in the binding to the SG promoter. The development of this system and the findings just described represent significant new developments in the alphavirus field. Publications Li, M-L., Lin, Y-H., Simmonds, H.A. and Stollar, V. (2004). A mutant of Sindbis virus

which is able to replicate in cells with reduced CTP makes a replicase/transcriptase with a reduced Km for CTP. J.Virol. 78, 9645-9651

Li, M-L., Lin,Y-H. and Stollar, V. (2005). A cell-free system for the synthesis of Sindbis

virus subgenomic RNA: Importance of the concentration of the initiating NTP. Virology, in press.

Teaching Microbiology and Immunology: First year course for medical students. Ethical Scientific Conduct, GSBS: IDST 5000 Case Based Learning: First year course for medical students. Invited Lectures 2005 lecture on Togaviruses for the Graduate Virology course at New York Medical

College in Valhalla, New York. February

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Honors Elected to the Stuart D. Cook Master Educators’ Guild of UMDNJ.

Seminars Sponsored Dr. John Taylor in Departmental Seminar Series. Feb, 2005 Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Postdoc: Tzu-Yu Huang Adjunct Ass’t Professor: Dr. Mei-Ling Li Technician: Yan Hu Administrative Committees Departmental Vice-Chairman Graduate Program in the Department of Molecular Genetics, Microbiology, and

Immunology (several committees). RWJMS Chairman, New Brunswick/Piscataway Campus Committee on Research Integrity Chairman, Admission Committee for MD-PhD students Elected member to the RWJMS Nominations Committee UMDNJ Investigative Panel evaluating a possible case of Scientific Misconduct. April-June 2005 Federal/State Appointments Ad hoc member, Virology Study Section, NIH. Feb, 2004. CDC panel evaluating grant applications dealing with West Nile virus. August, 2004 Editing/Consulting Journal Editorial Boards Member of Editorial Board, Journal of Virology, 1997-2005 Ad hoc reviewer for several other journals.

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Nancy Woychik, Ph.D. Research Activities In collaboration with Dr. Masayori Inouye and his laboratory in the Department of Biochemistry , Dr. Woychik is characterizing the function of families of toxin-antitoxin (TA) modules in Escherichia coli and Mycobacterium tuberculosis. She is also studying the effect of ectopic expression of individual bacterial TA toxins in Saccharomyces cerevisiae and exploiting toxin expression in yeast for the development of a novel protein expression system. Highlights of the Year This year marked the final transition process to new avenues of research with the addition of five new students, three Ph.D. and two M.S., to the laboratory. Through multiple collaborations, Dr. Woychik has shifted the focus of her work from fundamental mechanisms of transcription regulation to new research programs in bacterial toxin-antitoxin function and pathogenesis, protein expression technology and aging. Publications Articles Suzuki, M., Zhang, J., Liu, M., Woychik, N. A., and Inouye M. (2005) Single protein

production in living cells facilitated by an mRNA interferase. Mol. Cell 18, 253-261

Abstracts Prysak, M., Liu, M. Inouye, M. and Woychik, N. A. (2005) Analysis of bacterial toxin-

antitoxin expression in yeast. Yeast 22-Supplement 1 XXII International Conference on Yeast Genetics and Molecular Biology, Bratislava,

Slovak Republic, August 7-12, 2005 Teaching Microbiology & Immunology for Medical and Graduate Students 16:680:544/5 (MICR

6000) Sponsored Seminars "Endothelial Cell Growth and Differentiation in Hemangioma- An Endothelial Tumor that

Undergoes Spontaneous Regression" Dr. Joyce Bischoff, Harvard Medical School 3/8/05

Graduate Student Committee Memberships Loius Estrella/Hampsey laboratory-Ph.D. thesis defense committee member 7/19/04

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Jae-Ho Lee/Schiff laboratory-Biochemistry Ph.D. oral proposition exam member 8/10/04 Amit Balakrishnan/Fan laboratory-Ph.D. oral proposition exam member 1/15/05 Samual Bassous/Driscoll laboratory-Senior Honors thesis defense committee member

4/7/05 Laboratory Support Staff, Postdocs, Predocs, Visiting Scientists Lauren DeStefano-Ph.D. student Jennifer Hurley-Ph.D. student Mohan Liu-Ph.D. student Meredith Prysak-Ph.D. student Jared Sharp-Ph.D. student Nicolas Bauman-M.S. student Angela Cook-M.S. student Rohini Roy-M.S. student Lee Scozzare-M.S. student Carl Kunda-Rutgers undergraduate student Ekta Shah-Rutgers undergraduate student Administrative Committees Departmental Co-organizer, Departmental Seminar Series

Associate Director, Molecular Genetics, Microbiology & Immunology Graduate Program

Faculty Recruitment Committee Website Committee Seminar Committee

RWJMS Research Committee University

Physiology Chairman Review Committee for Dr. Nicola Partridge Executive Council, UMDNJ-GSBS Recruitment Committee, Molecular Biosciences Graduate Program

Curriculum Committee, Graduate Program in Molecular Genetics & Microbiology Community Involvement on Behalf of University Medical School Basic Research Advisory Group, New Jersey Commission on Cancer Research

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Editing/Consulting Editorial Board, Molecular and Cellular Biology Ad hoc Reviewer

FEMS Microbiology Letters Journal of Cell Science Genes & Development Molecular Microbiology

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Brief Research Interests

Joint, Adjunct & Volunteer Faculty

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Sefik S. Alkan, Ph.D. Research Activities We continued our studies on Immune Response Modifiers (IRMs). These synthetic molecules fall into three categories; Toll like receptor (TLR) 7 selective, TLR8 selective and TLR7/8 mixed agonists. They modulate the immune response both in vitro and in vivo. We have shown that TLR7 selective agonists preferentially stimulate plasmacytoid dendritic cells (pDCs) to secrete mainly IFN-a. TLR 8 selective agonists preferentially activate human myeloid dendritic cells (mDC) to secrete mainly TNF, IL-12 etc. We have also demonstrated that these TLR agonists indirectly activate T cells as well as NK cells. A recent publication indicates that they might affect the function of T regulatory cells (Peng. G., et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science. 2005 Aug 26;309(5739):1380). One of the TLR7 agonists, imiquimod (Aldara) is now approved for the treatment of genital warts, actinic keratosis and basal cell carcinoma. This year more evidence has been obtained indicating that TLR7/8 agonists exert better adjuvant effects when coupled to antigens such as HIV gag protein. (Wille-Reece U, et al. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15190). Taken together these studies indicate that IRMs are able to boost adaptive immunity via activation of innate immunity. Accumulating data clearly indicates that IRMs are good candidates for efficient vaccination, and immunotherapy of viral diseases as well as some cancers. Honors Invited speaker: Connecting innate and adaptive immunities via Toll like receptor agonists. Phacilitate Vaccine Forum 2004, Amsterdam, May, 10-13, 2004. Publications Keith Gorden, Kevin S. Gorski, Sheila J. Gibson, Ross M. Kedl, William C. Kieper,

Xiaohong Qiu, and Mark A. Tomai, Sefik S. Alkan, and John P. Vasilakos. Synthetic TLR Agonists Reveal Functional Differences Between Human TLR7 and TLR8 , J. Immunol., Feb 2005; 174: 1259 - 1268.

Cao, W, Chen Y, Alkan S, Subramaniam, A, Long F, Liu, H, Diao, R, Delohery, T,

McCormic, J, Chen, R, Ni, D, Wright, P, Zhang, X, Busch, S, Zilberstein A.: Human T helper cell lineage commitment is not directly linked to the secretion of Th cells isolated by FACS based on IFN-g and IL-4 secretion. Eur. J. Immunol. 35:2709-2717, 2005.

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Abstracts: John P. Vasilakos, Keith B. Gorden, Tanya L. Garrett, Sheila J. Gibson, Kevin S.

Gorski, Ross M. Kedl, Jacqueline Bjornton-Severson, Jana M. Lindh, Xiaohong Qiu, Mark A. Tomai, Lindsay R. Wurst, and Sefik S. Alkan. Synthetic TLR Agonists Reveal Functional Differences Between Human TLR7 and TLR8. 12th International Congress of Immunology, July 12-18 ,2004, Montreal, Canada

Kevin Gorski, Keith Gorden, Tanya Garrett, Xiaohong Qiu, Jacqueline Bjorton-

Severson, Emily Waller, Lindsay Wurst, Sheila Gibson, Sefik S. Alkan, John Vasilakos. TLR 8 agonists preferentially activate human myeloid dendritic cells and stimulate T-cell activation. 12th International Congress of Immunology, July 12-18, 2004, Montreal, Canada

Tony Riter, Sarah Asch, W. Chad Kieper, John Vasilakos, Sefik S. Alkan and Ross

Kedl. Co-delivery of Antigen and a TLR Agonist to the APC in vivo is More Critical Than Antigen Persistence for T cell Priming in a Vaccine Model. 12th International Congress of Immunology, July 12-18, 2004, Montreal, Canada

W. Cao, Y. Chen, S. Alkan, A. Subramaniam, et al. T helper cells lineage commitment

is not directly linked to the ability to secrete IF-g or IL-4: Transcript profile of cells sorted based on IFN-g and IL-4 production. Experimental Biology 2005, April 2-6, 2005, San Diego Convention Center, San Diego, CA.

Presentations Invited speaker: Utility of Immune Response Modifiers (TLR7/8) in Cancer Therapy, 7th

Annual Sabin Colloquium on Cancer Vaccines and Immunotherapy, Cold Spring Harbor Laboratory Genome Center, Woodbury, Long Island, NY June 21-24, 2005.

Invited speaker: Molecular Basis of Immunotherapies: War Against Allergy/Asthma and Cancer. The first Annual Conference of the Turkish-American Scientists and Scholars Association (TASSA), George Washington University on Washington, DC. February 19-20, 2005

David Beck, Ph.D. Research Activities In FY 2005, the Coriell Institute has expanded its stem cell biology research program, and Coriell faculty are now focusing on pancreatic, adipose, neuronal, hematopoietic, and muscle stem cells. In addition, the work begun last year to establish at Coriell the biomaterials resource for the international HAPMAP project, a major follow-on component of the human genome project, has expanded dramatically. Not only is Coriell responsible for collecting and distributing the biomaterials, but Coriell has now been chosen to handle the relationships with the subject communities. The New Jersey Cord Blood Bank (NJCBB), a public resource for umbilical cord blood

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stem cells for use in human hematopoietic reconstitution, and associated stem cell research programs, continues to grow, and it was refunded in the FY 2005 State of New Jersey budget. The NJCBB now contains well over 2000 units ready for transplantation and boasts seven apparently successful transplants. The Institute’s collaborations with RWJMS faculty continue to expand. Current collaborations include an NCI-funded breast cancer project, a DOD-funded prostate cancer project, and locally-funded efforts aimed at asthma, autism, gene therapy for neurological disorders, and stem cell biology. Internal Administrative Committees RWJMS Institutional Animal Care and Use Committee Committee on Continuing Medical Education at Cooper Hospital/UMC Institutional Biosafety Committee, Robert Wood Johnson Medical School at Camden,

Chairman UMDNJ President’s Strategic Planning Committee External Administrative Committees Member, New Jersey Commission on Science and Technology Member, Board of Directors, New Jersey Technology Council Member, Board of Directors, New Jersey Association for Biomedical Research Association for Independent Research Institutes, Past President; Chairman,

Membership Committee; member, Government Affairs Committee University of Pennsylvania Environmental Health and Safety Committee Fellow, College of Physicians of Philadelphia, Committee on Finance Burlington County College Program in Biotechnology Advisory Committee Member, Board of Directors, Chamber of Commerce Southern New Jersey Member, Board of Directors, Executive Service Corps Board of Directors Consulting and Public Speaking Private consulting to biotechnology managers Private consulting in research administration Public Lectures on Stem Cell Biology Bruce Byrne Ph.D. Research Activities Analysis of intron structure and evolution

Teaching Bioinformatics Core: Fall 2004 Fundamentals of Bioinformatics - GINF5001

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Special Topics in Bioinformatics – GINF 5030 Spring 2004

Fundamentals of Bioinformatics - GINF5001 Special Topics in Bioinformatics – GINF 5030

Graduate Committees: Nicholas Beckloff (Newark) Alexandra Oulianova (Newark) Peng Zhang (Piscataway) Qidong Zhang (Piscataway)

Publications

Byrne, B, Kerrigan, J and Golhar, R. A Secure Bioinformatics Linux Lab in an Educational Research Environment. Linux Journal http://www.linuxjournal.com/article.php?sid=7630. June, 2004.

Presentation

+NJEDge.NET Retreat: “Bioinformatics Training in a Secure Linux Environment” Service

Science Fair Judge, Corriell Institute for Medical Research; Camden County Administrative Committees University

AcITAC – IST Educational Resources Committee IST Research Resources Committee

Community Involvement on Behalf of University of Medical School

IRB: Coriell Institute for Medical Research NJEDge.NET Advisory Board – The State’s Higher Education Network

Treasurer C. Thomas Caskey, M.D. Dr. Caskey is the founding director of Houston-based Cogene Biotech Ventures and Cogene Ventures, venture capital funds supporting early-stage biotechnology and life sciences companies. The Cogene Biotech Ventures fund, founded in March 2000, invests in companies that utilize genome technology to enable drug discovery in high growth therapeutic specialties such as cancer, neurology and the metabolic diseases of obesity and diabetes. He served as President of the Texas Academy of Medicine,

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Engineering, and Science until Jan of 05 and is a member of the Scientific Advisory Board of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), part of The University of Texas Health Science Center at Houston. Dr. Caskey serves on Texas Governor Rick Perry’s Council on Science and Biotechnology, which makes funding recommendations for the $200 million Texas Emerging Technology Fund. Graham Cleaves, Ph.D.

Workshops

Conducted for teachers on how to teach AP Environmental Science.

Service N.J. Junior Academy of Science – Coordinated the organization and publication of the Junior Academy Abstracts for the 2005 Annual Meeting N.J. Academy of Science – member of the Steering Committee

Editing/Consulting

Editor – Cell Research Dalia Cohen, Ph.D. Research Activities: In Dr. Cohen’s position with Novartis she directs global research teams with laboratories in the United States and Switzerland specializing in Functional Genomics approaches. The main goal of the department is to identify novel therapeutic drug targets for unmet medical needs and providing them to Novartis core therapeutic areas for development. In addition, to enable the discovery of new drug targets in the post genomics era, major emphasis is given on the development of high-throughput in silico, in vitro and in vivo technologies for rapid triaging of potential targets. The department already provided potential drug targets for further development. In addition, Dr. Cohen runs an active laboratory. Her lab initiated the Histone deacetylate inhibitor program presently in Phase I. The department, with over 120 scientists, employed multi-disciplinary approaches in the functional genomics arena. These activities include Oligonucleotide Chemistry, Molecular and Cellular Biology, Proteomics, Model Organisms and Bioinformatics. Dr. Cohen’s laboratory is working on the following research: HDAC inhibitors are promising antitumor drugs, with several HDAC inhibitors already in

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clinical trials. LAQ824, a potent pan-HDAC inhibitor, has shown an ability to induce cell cycle arrest and cell death, therefore to repress tumor cell growth. The mechanisms of its antitumor effects, specially its tumor selective action, are still under active investigation. The focus of Dr. Cohen’s studies is to elucidate the molecular mechanism by which HDAC inhibitor mediates its selective anti-proliferative effects in cancer cells. She found that inhibition of HDAC activities by LAQ824 led to selective induction of apoptosis in human tumor cells but not in normal fibroblast cells. She also found that LAQ824 led to apoptosis via activating the mitochondrial death pathway by inducing Apaf1 and caspase 9 expression and activity, promoting mitochondria release of key proapoptotic factors such as cytochrome c and AIF in cancer cells but not in normal cells. Our results provided insight into the mechanism underlying the selective induction of apoptosis by LAQ824 in cancer cells. The dynamic balance between histone acetylation and deacetylation plays an important role in gene transcription regulation, DNA repair, replication and recombination. Histone deacetylase inhibitors, which potently induce growth arrest, differentiation and cell death, are now in phase I and phase II clinical trials. The action of HDAC inhibitors on gene expression appears to be selective, altering the transcription of only a limited number of genes in cultured tumor cells. The basis for this gene selectivity of HDAC inhibitors is unknown. To get insight into this selectivity, we utilized ChIP-on-Chip to perform a genome-wide study to investigate the status of histone H3 acetylation and binding patterns of RNA Pol II in about 15 K human gene genomic regions in lung cancer cells. We found that, at basal levels, significant histone H3 acetylation and RNA Pol II binding occur to the same set of genes, and both of them are indicators of transcription activity. Furthermore, we examined the changes in these binding patterns upon inhibition of HDACs by a potent pan-HDAC inhibitor, LAQ824. The results showed that LAQ824 treatment increased RNA Pol II binding over time. However, while LAQ824 treatment increased H3 acetylation within 30 minutes, longer LAQ824 treatments caused a loss of acetylation. Combined with the additional observation that the regions with histone H3 already acetylated were more prone to LAQ824 treatment, we propose that the regions, mainly composed of probes covering transcription start sites, contributed to the initial gain and subsequent loss of H3 acetylation. Gene function clustering data showed that cell cycle G1 phase related cyclin dependent kinase inhibitors, including p21Cip1, p19INK4d, p57Kip2 are targets of HDAC inhibitors in human lung cancer cells, explaining the G1 cell cycle arrest induced by LAQ824. These results give new insights into the mechanisms of HDAC-mediated transcriptional control and the potential therapeutic benefit of HDAC inhibition. Histone deacetylases (HDACs) play a critical role in regulating gene expression and key biological processes. Here, in this first systematic investigation of the role of HDACs in immunity, we show that a small molecule pan HDAC inhibitor (HDACi), LAQ824, alters TLR4-dependent activation and function of macrophages and dendritic cells (DC). Surprisingly, pan HDAC inhibition modulates only a small set of genes involved in distinct arms of immune responses. Specifically, it inhibited DC-controlled Th1 effector but not Th2 effector cell activation and migration. It also inhibited monocyte but not neutrophil chemotaxis. These unexpected findings demonstrate the high specificity of

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HDAC inhibition in modulating innate and adaptive immune responses, and highlight the potential for HDACi to alter the Th1 and Th2 balance in therapeutic settings. Teaching/Academic Appointments 2005- Vice President- Global Head Strategic and Enabling Technologies for Molecular Medicine Novartis Institute for Biomedical Research, Inc. (NIBRI) 1998- 2005 Vice President - Global Head of Functional Genomics Novartis Institute for Biomedical Research, Inc. (NIBRI) Novartis Pharmaceuticals Corporation 1998- Chairperson - Celera/Novartis Steering Committee 1998- Chairperson -Incyte/Novartis Steering Committee 1999- TSC – The SNPs Consortium - Member of the Board of Directors 2004- Harvard Science Technology (HST) MBA Student Committee Training Postdoctoral Fellows: 2001-2004 Alex Gaither, Ph.D. Novartis Institute for Biomedical Research 2001-2004 John Majercak, Ph.D. Novartis Institute for Biomedical Research Presentations: Genomics and Proteomics, Marcusevans Conference, Switzerland, (2002) Albert Einstein College of Medicine, Dept. of Molecular Pharmacology HDACs & Cancer

(2002) Japanese Society of Toxicology, Functional Genomics and Drug Discovery, Tokyo

(2002) Genomics on Target, From Function to Validation, Boston, Massachusetts (2002) Proposer and speaker, Novartis Foundation Symposium No. 259 on ‘Reversible

Acetylation of Chromatin and Non-Histone Proteins: Biology and Relevance to Human Disease’, London, UK (2003)

Genome Tri-Conference, Leveraging Functional Genomics Technologies to Meet the Needs of the Pharmaceutical Industry, Santa Clara, CA (2003)

SAPA 6th Annual Conference, Drug Discovery and Life Science 2003, Boston, MA (2003)

Genomics on Target Conference, Functional Genomics, Boston, MA (2003) Chips to Hits Conference, IBC Life Sciences 2003, Boston, MA (2003) Drug Discovery & Technology Leaders Summit, Oxford International, Orlando, Florida,

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(2004) The Global Translation of Science into Drug Development in Advancing Therapy, 2nd

Pharmaceutical Sciences World Congress, Kyoto, Japan (2004) World Drug Discovery & Development Summit, World Trade Company, Copenhagen,

Denmark (2004) R&D Leaders Forum, Phacilitate Limited, Coral Gables, Florida, (2004) Drugs In the Postgenomics Era - ETH, Swiss Federal Institute of Technology Zurich

Switzerland (2005) Proteomics & Bioinformatics , Keystone Conference, Keystone Colorado ( 2005)

University of Geneva, Geneva Switzerland (2005) Publications: Marjercak, J., Dengler, U., Reinhardt, R., Konsolaki, M., Cohen, D. Ankyrin G is a

marker for Alzheimer’s disease neurodegeneration (under review). Invited Papers/Reviews Konsolaki,M. and Cohen, D. Review for Targets: Innovations in Genomics &

Proteomics: Targets for Alzheimers: lessons learnt from flies, Drug Discovery Today 3; 64-69, 2004

Wang, S., Neale, Y.Y., Zeremski, M., Cohen, D, Transcription Regulation by Histone Deacetylases, Novartis Foundation, 2004, Reversible protein acetylation. Wiley,Chichester (Novartis Foundation Symposium 259), pg. 238-248

Cohen, D., PharmaTech Series Business Briefing, Future Drug Discovery, 2004

Fischer, V., Einolf, H.J., and Cohen, D., Efflux Transporters and their Clinical Relevance, Communicated in Current Medical Chemistry, (in press)

Atadja, P., Gao, L., Kwon, P., Trogani, N., Walker, H., Hsu, M., Yeleswarapu, L., Chandramouli, N., Perez, L., Versace, R., Wu, A., Sambucetti, L., Lassota, P., Cohen, D., Bair, K., Wood, A., Remiszewski, S., 2004. Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor NVP-LAQ824. Cancer Research, 64:689-695

Dieter Huesken, Joerg Lange, Craig Mickanin , Jan Weiler, Fred Asselbergs, Justin Warner, Brian Meloon, Sharron Engel, Avi Rosenberg, Dalia Cohen, Mark Labow, Mischa Reinhardt, François Natt and Jonathan Hall An artificial neural network for the design of a genome-wide siRNA library. Nature Biotechnology, 23:995-1001, 2005

Advisory/Editorial Boards 2001- Pharmaceutical Advisory Board, Cambridge Healthtech Institute 2002- PharmaGenomics Editorial Board 2002- Phacilitate PWC Consulting Advisory Board

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2002- Cell Cycle Editorial Board 2003- Business Briefing: Future Drug Discovery 2003- Genome Technology Editorial Advisor Jeffry R. Cook, Ph.D. Research Activities Protein methylation has been shown to occur in a number of diverse biological processes such as signal transduction, chromatin remodeling, RNA splicing, RNA decay, gene regulation, nuclear export of proteins, inhibition of oncogenic ras signal transduction, and bacterial chemotaxis. The methylation of protein substrates is

catalyzed by enzymes that transfer a methyl group from S-adenosylmethionine to a protein acceptor, a process that occurs in many organisms. The residues that are modified by methylation include arginine, histidine, lysine, and aspartic acid. Protein-arginine methyltransferases (PRMTs)1 catalyze the formation of methylarginine residues. Four types of protein arginine methyltransferases have been described. Type I PRMTs form ω-NG-monomethylarginine and asymmetric ω-NG,NG-dimethylarginine (ADMA) residues; type II PRMTs form ω-NG-monomethylarginine and symmetric ω-NG,NG'-dimethylarginine (SDMA) residues; type III and type IV PRMTs synthesize only δ-NG-monomethylarginine (MMA) and ω-NG-monomethylarginine, respectively. Although the presence of SDMA in eukaryotic cells has been known for a number of years, an enzyme that could synthesize SDMA was first identified by Pollack, Pestka et al. It was subsequently characterized and designated PRMT5. PRMT5 was found to methylate histones H2A and H4, myelin basic protein (MBP), and several spliceosomal Sm proteins (SmD1, SmD3 and SmB) in vitro. Methylation of spliceosomal components by PRMT5 is a prerequisite for their assembly into the spliceosome. PRMT5 also has been shown to be associated with the cyclin E gene and to be involved with other transcriptional events as well. Although a large number of proteins have been found to contain SDMA residues, for several years PRMT5 was the only known Type II PRMT. During the past year we reported the discovery of two other Type II protein arginine methyltransferase, PRMT7 and PRMT8, both of which can synthesize SDMA. PRMT7 was initially characterized in hamster cells as a protein that modulates drug sensitivity to DNA-damaging agents. We have now established that PRMT7 can methylate histones, SmD3 and peptides containing a GRG motif in vitro. However, the proteins that are methylated by PRMT7 in the cell remain to be identified. PRMT8 is also known as FBXO11 due to the presence of an F-box motif in the protein. F-box proteins are known to be involved in ubiquitination and this fact strongly suggests that PRMT8 has a role in this process. A third enzyme producing SDMA was identified in yeast. We demonstrated that Hsl7p is an active protein arginine methyltransferase a number of years ago. The fact that we have now identified a PRMT (Hsl7p) that forms SDMA in yeast indicates that the ability to form this posttranscriptional modification has a lengthy phylogenetic history. Our

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most recent work in collaboiration with Dr. Michael Bedford (M. D. Anderson) involves the examination of the effects of protein methylation inhibitors on ADMA, SDMA and MMA production in mammalian cells. In addition, we have examined PRMT5 null mice in collaboration with Dr. Paul Maletesta of UMDNJ and Dr. Steven Young at UCSF and have shown that disruption of the PRMT5 gene results in lethality at the blastocyst stage of development. Key participants in these projects include Dr. Sidney Pestka, Dr. Jin-Hyung Lee and Zhi-Hong Yang. Teaching Departmental medical microbiology course

Publications Kim, Y., Izotova, L., Yang, Z., Mirochinitchenko. Lee, J.H., Cook. J.R., Branscombe

T.L., Clarke, S. and Pestka, S. (2004) MEP50, a stimulator of methyltransferase activity of protein arginine methyltransferase 5. J. Interferon Cytokine Res., Suppl. (Abstract).

Lee, J.-H., Cook, J.R., Mirochnitchenko, O., Gunderson, S., Felix, A., Hoffman, R.,

Herth, N. and Pestka, S. (2004) Identification and characterization of a new protein arginine methyltransferase, PRMT7, J. Interferon Cytokine Res., Suppl. (Abstract).

Miranda, T. B., Khusial, P., Cook, J.R., Lee, J.-H., Gunderson, S.I., Pestka, S., Zieve,

G.W. and Clarke, S. (2004) Spliceosome Sm proteins D1, D3 and B/B’ are asymmetrically dimethylated at arginine residues in the nucleus. Biochem. Biophys. Res. Commun. 323, 382-387.

Lee, J.H., Cook, J.R., Yang, Z.-H., Mirochnitchenko, O, Gunderson, S., Felix, A.,

Hoffman, R., Herth, N. and Pestka, S. (2004) PRMT7: A new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J. Biol. Chem. 280, 3656-3664.

Service Director of MGMI Phosphorimaging Facility

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Lori R. Covey, Ph.D. Research Activities The research in my laboratory focuses on mechanisms that regulate the humoral immune response. Specifically, we are interested in understanding how signals delivered by CD40 ligand (CD40L or CD154) expressed on T cells activate CD40-expressing B cells to undergo differentiation and express all classes of antibodies. In our ongoing efforts to understand how CD40-mediated signals translate into differentiation-related events at the human immunoglobulin heavy chain (IgH) locus, we have identified a patient (pt#1) with non-X-linked hyper-IgM (HIM) syndrome who has B cell defects in CD40-mediated signaling. Our findings with pt#1 B cells supports a model whereby a molecule or transcription factor in the IL-4 and CD40 signal transduction pathway is directly altered by the pt#1 mutation and that the altered factor is critical for CSR and the expression of IgG, IgA and IgE isotypes. A critical aspect of regulating the CD40 response in B cells is through availability of its ligand, CD154 expressed on activated CD4+ T cells. Since CD40 is constitutively expressed on all classes of B cells and other antigen presenting cells (APCs), regulation of CD154 expression becomes a pivotal step in controlling the specificity and scope of the humoral and cell-mediated immune responses. We have discovered that CD154 is regulated at the post-transcriptional level by a mechanism of “regulated instability” throughout a time course of CD3 or CD3 plus CD28 activation. This non-ARE pathway of regulated mRNA decay in T cell activation had not been previously reported. We have extended our initial findings by identifying a T cell activation-dependent complex (termed Complex I) that binds specifically to a region of the CD154 3'UTR and mediates message stability. Also, we have shown that polypyrimidine tract protein (PTB) is a major component of Complex I and that nucleolin is a second component that interacts with both PTB and the Complex I binding site. Together, these data indicate that the regulated decay pathway of CD154 mRNA decay is a novel, non-ARE pathway mediating mRNA stability during T cell activation. We are currently determining why Complex I activity is present in late but not early activated T cells and identifying other transcripts that are regulated by this activation-induced complex. Teaching 2001-present Lecturer, Cell & Develop. Immunology (graduate) 2005-present Organizer & instructor, Immunology Lecture Course (undergrad) Dept. of

Cell Biol & Neuro., 146:474 1994-present Organizer & instructor, Immunology Lab Course (undergrad) Dept. of Cell

Biol & Neuro. 146:475 Publications Singh, K., J. Laughlin, P. Kosinski and L. R. Covey. 2004. Nucleolin is a second

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component of the CD154 mRNA stability complex that regulates mRNA turnover in activated T cells. J. Immunol. 173:976-85. Presentation “Transcriptional activation of the Ig1 promoter is mediated by p300/CBP”, mini-symposium Experimental Biology, 2005, San Diego, CA, April 2-6, 2005. Service 2003-2006 Member, Committee on the Status of Women- American Assoc. of Immunologists 2005 Member, Genetics Search Committee Administrative Committees Ph.D. Thesis Committee Member 2004 Yujie Zhao (Dr. Arnold Rabson) 2004 Subarna Khan (Dr. David Denhardt) 2004 Naomi Bergman (Dr. Jeff Wilusz, UMDNM, Newark) 2005 Hudan Liu (Dr. Mike Kiledjian) M.S. Thesis Committee Member 2004 Lynn Lagos (mentor: Dr. Celine Gelinas) 2004 Kathleen Kelly-Borja (mentor: Dr. Mike Kiledjian) 2004 Katie Doktor (mentor: Dr. Arnold Rabson) 2005 Teletha A. Brown (mentor: Dr. Emmet Dennis) 2005 Hal Woodrow (mentor: Dr. Howard Passmore) Editing/Consulting Ad hoc reviewer for: Journal of Immunology International Immunopharmacology Cellular Immunology Immunobiology Journal of Experimental Medicine American Journal of Pathology Molecular and Cellular Biology BBA-Gene Structure and Expression International Immunology Clinical Immunology Jonathan Dinman, Ph.D Research Activities We focus on three specific research aspects under the broad umbrella of “translational control”. First, a combined genetic, biochemical, and molecular approach is being used

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to elucidate the relationship between ribosome structure and function. The second area of research centers on identifying and characterizing the role that programmed -1 ribosomal frameshifting plays in regulating the expression of cellular genes. Thirdly, we are investigating the role played by programmed -1 ribosomal frameshifting in the life cycle of the SARS-associated coronavirus.

Teaching (at University of Maryland) Department of Cell Biology and Molecular Genetics. Virology (BSCI437). Department of Cell Biology and Molecular Genetics. Genetics I: Gene Expression

(CBMG688F). Department of Cell Biology and Molecular Genetics. Graduate Virology (BSCI688). Department of Cell Biology and Molecular Genetics. Special Problems in Cell Biology

and Molecular Genetics: Protein Translation (CBMG699Z). Department of Cell Biology and Molecular Genetics. Current Topics in Virology (MICB

688U). Publications Petrov, A., Meskauskas, A., and Dinman, J.D. Ribosomal protein L3: influence on

ribosome structure and function. RNA Biology, 2004; 1: 59-65. Harger, J.W. and Dinman, J.D. 2004. Evidence against a direct role for the Upf

proteins in frameshifting or nonsense codon readthrough. RNA 10:1721-1729. Jacobs, J.L. and Dinman, J.D. 2004. Systematic analysis of bicistronic reporter assay

data. Nucleic Acids Research 32:e160-70. Plant, E.P. and Dinman, J.D. 2005. Torsional restraint: a new twist on frameshifting

pseudoknots. Nucleic Acids Research, 33:1825-33. Plant, E.P., Perez-Alvarado, G, Jacobs, J.L., Mukhopadhyay, B., Hennig, M., and

Dinman, J.D. 2005. A three-stemmed mRNA pseudoknot in the SARS coronavirus frameshift signal. PLoS Biology, 3:1012-1023.

Presentations University of Maryland, Chemistry & Biochemistry Departmental Seminar. The University of Nebraska School of Biological Sciences. Department of Chemistry, Moscow State University, Moscow, Russia. Cold Spring Harbor Meeting on Translational Control. Cold Spring Harbor, NY. Division of Viral Products, Food and Drug Administration. George Washington University Department of Biochemistry. NIH, Washington Area Yeast Interest Group.

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Honors 2004.University of Maryland College of Life Sciences Faculty Excellence Award for

Research. 2004. Outstanding Invention of 2003, Life Sciences. University of Maryland Office of

Technology Commercialization, Research and Graduate Studies. Service NIH ZRG1 ICM-B (90). Special Emphasis Panel on Prions. April 8, 2005. NIH ZRG BPC-Q (40). Special Emphasis Panel Mechanism of Translation. Dec. 7,

2004. NIH Biophysical and Biochemical Fellowships Review Panel, November, 2004. NHGRI Special Emphasis Panel ZHG1 HGR-P (01) ENCODE RFA review, June 2004. NIH Physiological Chemistry Study Section (PC), June, 2003; February, 2004. Editor-in-Chief, International Journal of Biomedical Science Trustee, The Stamm Foundation for Holocaust Studies. Administrative Committees Departmental (at University of Maryland) CBMG Awards Committee CBMG Committee on Adjunct and Affiliate Faculty. CBMG Graduate Program Committee. CBMG Faculty Search Committee, Comparative and Functional Genomics. CBMG Long Range Planning Committee: Immunology and Pathogenesis. University (at University of Maryland) College of Chemical and Life Sciences Junior Faculty and Research Awards

Committee. 2005. College of Chemical and Life Sciences CBMG Chairman search committee. Spring, 2004.

MOCB Seminar series coordinator, Spring 2005, 2006. Virology Graduate Training Program Fellowships Committee. University of Maryland Senate Academic Procedures and Standards Committee.

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Ellen C. Ebert, M.D. Research Activities My laboratory studies the functions of human intestinal intraepithelial lymphocytes (IELs), located between epithelial cells (ECs) throughout the gastrointestinal tract. These CD8+ IELs are distinctly different from CD8+ T cells found in peripheral blood. Phenotypically, they have markers of memory cells. Functionally, they have a pronounced ability to destroy EC tumors such as colon cancer. Since tumor-infiltrating lymphocytes have similar phenotypic and functional features as IELs, they may be derived largely from the adjacent IEL population. Teaching Second-year pathophysiology course for medical students Publications E. C. Ebert. IL-15 converts human intestinal intraepithelial lymphocytes to CD94+

producers of IFNγ and IL-10, the latter promoting fas ligand-mediated cytotoxicity. Immunology 115:118-126, 2005.

E.C. Ebert, V Mehta, KM Das. Activation antigens on colonic T cells in inflammatory

bowel disease: effects of IL-10. Clin Exp Immunol 140:157-165, 2005. E.C. Ebert. Endogenous inhibitory cytokines repress TNFα secretion. Cell Immunol (in

press) E.C. Ebert CD2 activation of human lamina propria lymphocytes reduces CD3

responsiveness. Immunol 117:71-77, 2005. E.C. Ebert. Gastrointestinal complications of diabetes mellitus. Disease-a-Month

51:620-663, 2005 Presentation E.C. Ebert. Alefacept reduces constitutive CD2-mediated interferon (IFN)-gamma

production by lamina propria lymphocytes in Crohn’s disease. Oral presentation at AGA 2005

E.C. Ebert, X Geng, A Panja, J Liu, KM Das. Sera from active ulcerative colitis contain

IgG antibodies against human tropomyosin isoform 5 (hTM5) that kill normal colonic epithelial cells. Poster presentation at AGA 2005.

E.C. Ebert, B Jabri. TCR-independent IL-15-induced interferon-gamma production by

lamina propria lymphocytes is transiently upregulated by IL-12. Poster presentation at AGA 2005.

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Service Director of Educational activities for gastroenterology Administrative Committees Departmental

RWJMS: Charity care committee EVELYN S. ERENRICH Grants and Awards Assistant Dean Evelyn S. Erenrich serves as Program Director for the Piscataway campus for the Northeast Alliance for Graduate Education and the Professoriate, a consortium award from the National Science Foundation, was renewed with substantially increased funding. Our campus will receive $132,500 per year for the next 5 years (2005-2009) under a sub-contract. Dr. Erenrich received an award for $28,267 from the Federation of American Societies for Experimental Biology (FASEB) to support students in the RISE (Research In Science and Engineering) at Rutgers/UMDNJ summer program. RISE, co-directed by Dr. Erenrich and Dr. Jerome Langer, has been highly successful in preparing students for graduate studies and has become a major source of successful applicants to our Ph.D. programs. Dr. Erenrich initiated and facilitated applications for minority supplements to NIH grants to support scholars in RISE at Rutgers/UMDNJ : Dr. Patrizia Casaccia-Bonnefil, NINDS, $4000 and Dr. John Pintar, $4000 She also facilitated student travel awards to the Annual Biomedical Research Conference for Minority Students (ABRCMS), totaling $3600. Other Achievements/Activities Dr. Erenrich was invited by Dr. Denise Rodgers to be a member of the RWJMS Strategic Planning Committee, Promoting Diversity Subcommittee. She chaired the Molecular Biosciences Admissions Committee Diversity Subcommittee. She was invited to participate in the NSF site visit of IGERT Training Grant on Biointerfaces. Based on the programmatic synergies and leveraging of resources that she has led on the Piscataway campus, the IGERT national leadership is showcasing us as a national model.

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Dr. Erenrich led a team of graduate students to the second annual Northeast Science Days. Michael Bryan, a graduate student with Dr. Barbara Brodsky, won first prize in the poster competition. Presentations and Publications: Jerome A. Langer, Evelyn S. Erenrich, Mildred Chaparro, Bonnie Lustigman and

Michael J. Leibowitz, “The Unified Plan: Interweaving M.S./Ph.D. Bridge Programs with Graduate and Undergraduate Components of an IMSD Program,” presented at the NIH Bridges Program Directors Meeting, Denver, Colorado, July 8, 2004.

Evelyn S. Erenrich, Jerome A. Langer and Michael J. Leibowitz, “Paving the Pathway to Graduate School: The Roles of a Summer Undergraduate Research Experience,” presented at the Yale Bouchet Conference on Diversity in Graduate Education, New Haven, CT, April 1, 2005.

Evelyn S. Erenrich, Jerome A. Langer, Linda J. Anthony, Janice Johnson and Michael J. Leibowitz, “Extending the Scope of a Summer Undergraduate Research Program through Collaborations,” presented at the UMDNJ Master Educators Guild Symposium, Piscataway, New Jersey, April 7, 2005.

Jolie A. Cizewski, Evelyn S. Erenrich, Jerome A. Langer, and Michael J. Leibowitz, ‘Paving the Pathway to PhD Studies in the Sciences,” presented by invitation by Dr. Cizewski at the Center for the Integration of Research, Teaching, and Learning (CIRTL), University of Wisconsin, May 2005.

On-Campus Invited Talks “Graduate School and Research Careers,” presented at ODASIS (Office of Diversity

and Academic Success in the Sciences,” October 14, 2004. “Graduate School in the Sciences, Math, and Engineering,” presented to Douglass

College Bunting-Cobb Scholars, November 16, 2004. Recruitment Conferences Florida Georgia Louis Stokes Alliance for Minority Participation, January 2005 Annual Biomedical Research Conference for Minority Students (ABRCMS), November

2004 National Society for Black Physicists and Physics Students, February 2005 Campus Visits Delaware State University, October 2004 University of Delaware, October 2004 Puerto Rico – 8 colleges and universities, November 2004

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University of Maryland, Baltimore County – December 2004 Hunter College, January 2005 Arthur M. Felix, Ph.D.

Research Activities Synthesis of branched pegylating reagents containing glycyl spacers Pegylation of aspirin and its derivatives Teaching Courses taught (fall’04) Ramapo College of New Jersey SCHM 210.01 (Organic Chemistry I) SCHM 210.02 (Organic Chemistry I) SCHM 111.01 (Fundamentals of Chemistry Laboratory I) SCHM 425.01 (Biochemistry) Courses taught (spring’05) Ramapo College of New Jersey SCHM 212.01 (Organic Chemistry II) SCHM 212.02 (Organic Chemistry II) SCHM 426.01 (Experimental Biochemistry Laboratory) Publications J.-H. Lee, J.R. Cook, O. Mirochnitchenko, S. Gunderson, A.M. Felix, N. Herth, R.

Hoffmann and S. Pestka, J. Biol. Chem., 380, 3656 (2005). PRMT7: A New Protein Arginine Methyltransferase that Synthesizes Symmetric Dimethyarginine.

A.M. Felix and R.M. Bandaranayake, J. Pept. Res., 65, 71 (2005). Synthesis of Bis-

and Tris-Branched COOH-Terminal Pegylating Reagents: Conjugation to NH2-Terminal Peptides.

Presentations A. Carbone and A.M. Felix. “Enzyme Catalyzed Pegylation of Insulin Fragments: Model

Compounds for Site-Specific Pegylation of Insulin.” 53rd Annual Undergraduate Research Symposium, SUNY-Stony Brook, NY; May, 2005.

V. Popov and A.M. Felix. “Synthesis of NH2-Terminal and COOH-Terminal Branched

Pegylating Reagents.” 53rd Annual Undergraduate Research Symposium, SUNY-Stony Brook, NY; May, 2005.

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Service – At Ramapo College All-College Promotions Committee Unit Personnel Committee Convener of Chemistry Editing/Consulting

Journal Editorial Boards Peptide Science Journal of Peptide Research Analytical Biochemistry Organic Preparations and Procedures International Editor

Synthesis of Peptides & Peptidomimetics, Publisher: Houben Weyl (Stuttgart, Germany).

Patents Arthur M. Felix and Robert E. Martin, “Water Soluble Aspirin Formulation with Enhanced

Stability and Bioactivity” U.S. Pat. (submitted, June, 2005). Janusz J. Godyn, MD Research Activities Dr. Godyn has developed a remarkable program of pathology services at our affiliate hospitals. He has solidified pathology services and laboratory medicine supervision at three community hospitals and several community laboratories, in addition to the primary RWJ University Hospital. RWJ faculty members under Dr. Godyn’s mentorship took over the leadership of Performance Improvement Committees and Tissue & Transfusion Committees, and exercised significant influence over Infection Control Committees, Cancer Committees, Bylaws Committees Nominating committees and Credentials Committees. Participation in Medical Executive Committees in all the three community hospitals has been a part of the community service process. Staff in the Group is highly racially and culturally diversified (includes African-American, Spanish American, European-American, European, African, Indian and Oriental members). Teaching All the faculty members are constantly mentored for laboratory directorships: two were prepared and promoted to laboratory director positions (Bayshore and Bristol Myers

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Squibb) and one to the associate director of laboratory (ICON). Lectures included to Sophomore Medical Students in Microbiology Course organized by the Department of Molecular Genetics, Microbiology and Immunology, RWJMS. Students from the Mercer County Community College in Medical Technology program who rotated at RWJUH at Hamilton praised the pathologist mentorship there and successfully passed the national exam. Clinical-Pathologic conferences, Tumor Boards, extensive phone consultations on clinical/pathological issues for community physicians. Visiting lecturer abroad on clinical and quality in health care issues.

New CME programs at RWJUH - Hamilton were highly rated by practicing physician participants from Mercer, Burlington, Monmouth and Ocean Counties:

1/ Anthrax – a review illustrated by clinical cases 2/ Gastroduodenal Diseases 3/ Cytopathology - Diagnostic Accuracy 4/ Colitis with Bloody Diarrhea

Publications Godyn JJ, Dotsey B. Prevalence of presumptive Bacillus anthracis in human population

examined by nasal swabs. Am J Infect Control 2004; 34(6):355-357. Godyn JJ, Ryes L, Siderits R, Hazra A. Cutaneous Anthrax – Conservative or surgical

treatment? Advances in Skin & Wound Care 2005; 18 (3):146-150. Godyn JJ. Heading-off Anthrax at Hamilton, New Jersey. Events of October 2001. New

Jersey Medicine 2005; 102 (1-2):51-54. Godyn JJ, Siderits R, Hazra A. Schistosoma mansoni in colon and liver. Arch Pathol

Lab Med 2005; 129 (3): 544-555. Hazra A, Ricart C, Godyn JJ. Clinical significance of Helicobacter heilmannii colonizing

human gastric antrum. Practical Gastroenterology 2005; in press Godyn JJ, Hazra A, Gulli V. Subperitoneal placenta accreta succenturiate in a case of

the successful near-term extrauterine abdominal pregnancy. Human Pathology 2005; in press

Siderits R, Dikon A, Ouattara O, Godyn JJ. Preparation and use of Scabies skin

scraping kits. Advances in Skin & Wound Care 2005; in press Hazra A, Siderits R, Godyn JJ. Hypereosinophilic syndrome associated with cervical

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squamous cell carcinoma. The Female Patient 2005; in press Godyn JJ. Laboratory Quality Pillars at the Baldrige-winning Hospital. Leadership

Outlook. Advance for the Administrators of the Laboratory 2005; in press Other research activities: Provisional Patent Application:

Siderits R, Godyn JJ. Disposable Grossing Station (in review) Funding Pittsburgh Supercomputing center, 5/04 - present: Siderits, R. and Godyn, J. Proposal/Grant Number: BIO040001P Proposal Title: Tissue kinetics model for artificial cell/tissue array constructs. Synopsis: Mutable heuristic parabiotic OO-oriented 3&4 dimensional Digital Bio-Domain

constructs. Bayshore Hospital Laboratory directed by Dr. Godyn, participated in the following

clinical studies: “Phase” randomized, double-blind, multi-center study to evaluate safety and efficiency

of Dalbavanic versus Linezolid in the treatment of complicated skin and soft tissue infections with suspected or confirmed gram-positive bacterial pathogens”

“A study of avelox for treatment of elderly patients with community acquired pneumonia” “Prospective, open label non-comparative, multicenter trail to evaluate the efficiency

and safety of Ciprofloxacin extended-release in the treatment of female patients with acute, uncomplicated, symptomatic, lower urinary tract infections”

Service Chairman, Department of Pathology, RWJ University Hospital at Hamilton Chairman, Department of Pathology, Bayshore Community Hospital at Holmdel Chairman, Department of Pathology & Laboratory Medicine, Southern Ocean County

Hospital at Manahwakin Laboratory Director, Cancer Institute of New Jersey at Hamilton Laboratory Director, Health & Wellness Center, Hamilton Laboratory Director, Bayshore Community Hospital (until 12/2004) The physician services were rated at RWJUH at Hamilton by the Jackson Organization at the beginning of 2005. The laboratory services at RWJUH at Hamilton supervised by Dr. Godyn were rated for quality performance with the Mean of 3.90 while the Jackson

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National Database Mean was 3.70. This placed us in 80th percentile, and it was statistically significantly higher than the National Mean. The pathologists were overall rated with the Mean of 3.93 while the Jackson National Database Mean was 3.78. Administrative Committees Board of Directors, RWJ Health Network Physician Coordinating Council, RWJ Health Network Strategic Business Development and Planning Committee, UMG Professional Affairs Committee, Board of Trustees, RWJ Hamilton Quality Oversight Committee, Board of Trustees, RWJ Hamilton Medical Executive Committee, RWJ Hamilton Performance Improvement Committee, RWJ Hamilton, Chairman Cancer Committee, RWJ Hamilton Infection Control Committee, RWJ Hamilton CME and Library Committee, RWJ Hamilton, Medical Quality Council, RWJ Hamilton Peer Review Committee (B), RWJ Hamilton Transfusion Committee, RWJ Hamilton Institute for Excellence, RWJ Hamilton Bylaws Committee. RWJ Hamilton Medical Executive Committee, Bayshore Hospital. Credentials Committee, Bayshore Hospita PI Committee, Bayshore Hospita Cancer Committee, Bayshore Hospital Infection Control Committee, Bayshore Hospita Tissue & Transfusion Committee, Bayshore Hospita Quality Oversight Committee. Bayshore Hospita Medical Executive Com, Southern Ocean County Hospital Credentials Committee SOCH – Past Chairman Inspector for the College of American Pathologists Advisory Committee for Medical Technology Program, Mercer County Community

College. Honors Dr. Godyn was a significant participant in Excellence Through Service program of Quality and Performance Improvement at RWJUH at Hamilton, the first and only New Jersey hospital-recipient of Malcolm Baldrige National Quality Award (U.S. Presidential Award) for 2004.

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RWJUH at Hamilton was also a recipient of New Jersey Quality - Gold Level, the NJ State Governor’s Award for 2004. Dr. Godyn was a significant contributor to the team work leading to that Award, too. Dr. Godyn has been the Chairman of Performance Improvement Committee of RWJUHH at Hamilton, and he was a member of the delegation of RWJUH at Hamilton which went to Washington, DC, to accept the National Quality Award from Vice President Cheney and Secretary of Commerce Gutierrez in 2005. Alice B. Gottlieb, MD, PH.D. Research activities Dr. Gottlieb is a Professor of Medicine and Founding Director of the Psoriasis Center of Excellence at UMDNJ-Robert Wood Johnson Medical School, where she has presided in the past year over more than $1,500,000 in grant funding as principal investigator. Her research using targeted immunobiologics as pathogenic probes, provided new understanding of the pathogenesis of psoriasis and provided the foundation for biologic drug development in psoriasis and psoriatic arthritis. She has authored 120 peer-reviewed articles that have appeared in journals such as The Lancet, the New England Journal of Medicine, Nature: Drug Discovery, Proceedings of the National Academy of Sciences, Journal of Experimental Medicine, Archives of Dermatology, the Journal of the American Academy of Dermatology, and Journal of Investigative Dermatology. She has presented her research at more than 200 dermatology and rheumatology conferences in Europe, Asia and the United States, as well as at the FDA and the National Academy of Sciences. She is on almost every list of outstanding doctors, including Cambridge’s International Biographical Centre’s “Leading Health Professionals in the World,” Castle Connolly’s Top Doctors: New York Metro Area, and “Best Doctors in America.” She is triple boarded in dermatology, rheumatology and internal medicine, and is one of only a handful of doctors in the United States to be certified in all three of these specialties. Dr. Gottlieb has received numerous awards for mentoring and teaching including Honorary Membership in Alpha Omega Alpha in recognition of medical student teaching, a Research Mentorship award from the Internal Medicine house staff and a Mentorship Award from the American Chemical Society for mentoring minority high school students in bench and clinical research. Dr. Gottlieb is a member of the American Dermatological Association and Noah Worcester Dermatology Society amongst other professional societies. She was one of the first scientists to demonstrate that psoriasis is a T cell mediated disease. She initially demonstrated increased numbers of activated T cells and increased expression of a number of immunologic cytokines in psoriatic plaques (reported in multiple publications, e.g., the Journal of Experimental Medicine, Proceedings of the National Academy of Sciences). She then showed that treatment with a T cell-specific immunotoxin cleared psoriasis clinically and histologically (published in Nature Medicine and noted in commentary in The Lancet). Dr. Gottlieb,

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through her published studies and public presentations, has convinced a number of pharmaceutical companies to use psoriasis as their proof-of-concept disease when testing new immunomodulators that may decrease TH1 cytokine production. Thus, her work has affected drug development in psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and transplantation. As a direct result of Dr. Gottlieb’s work, many biotechnology-engineered immunomodulators are FDA and /or EMEA-approved for psoriasis and psoriatic arthritis. Currently, Dr. Gottlieb’s research centers on developing new treatments for psoriasis and psoriatic arthritis and on understanding the mechanisms of action of these novel agents. Her laboratory works involves the study of apoptosis and inflammation-related protein and gene expression in patients responding to novel psoriasis treatments. She is a leading educator in her specialties, and continues at the forefront of mentoring female and minority students and overseeing community outreach and patient advocacy programs. She is active in the autoimmune disease community as a councilor of the International Psoriasis Council and a member of the Steering Committee of GRAPPA (an international psoriatic arthritis coalition) and Co-Editor of the Psoriasis Forum, the physicians’ newsletter of the National Psoriasis Foundation. Suhayl Dhib-Jalbut, MD Research activities My Laboratory continues to investigate the mechanisms of action immunomodulatory drugs in multiple sclerosis including the Interferon-betas and Glatiramer acetate. Some of the immunological changes observed in treated patients are being examined prospectively as potential biomarkers of response to therapy. We are utilizing adult mouse bone marrow stem cells as vehicles to deliver the Interferon-beta gene into the brain and examine the therapeutic effect of this approach in experimental autoimmune encephalomyelitis (EAE). Preliminary results suggest an effect on relapses in EAE. We are utilizing the same approach to deliver neurotrophic gene products such as BDNF, into the CNS and are assessing the effect on neuronal and axonal survival in EAE. Current funding 5/99-4/06 NIH/NINDS: K24 NS 02082 Award. Therapeutic mechanisms of Interferon-ß and Copolymer-I in Multiple Sclerosis, PI: Suhayl Dhib-Jalbut, MD $544,000 9/01-9/06 Interferon-ß gene therapy in an animal model of multiple sclerosis Sponsor: National Multiple Sclerosis Society

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PI: Suhayl Dhib-Jalbut, MD $461,624 3/02-2/06 Predictors of clinical response to Glatiramer acetate in MS. Sponsor: The Wadsworth Foundation PI: Suhayl Dhib-Jalbut, MD $300,000 10/1/04-9/30/07 Laboratory Surrogate Markers of Clinical Response to Glatiramer

Acetate (Copaxone) in Multiple Sclerosis Sponsor: TEVA Industries PI: Suhayl Dhib-Jalbut, MD $335,000

Teaching Neurology Clerkship for III-year medical students Publications Makar TK, Trisler D, Eglitis MA, Mouradian MM, Dhib-Jalbut S. Brain-derived

neurotrophic factor (BDNF) gene delivery into the CNS using bone marrow cells as vehicles in mice. Neuroscience Letters 356:215-219, 2004.

Graber J, Zhan M, Ford D, Kursch F, Francis G, Bever C, Panitch H, Calabresi PA,

Dhib-Jalbut S. Interferon-ß-1a induces increases in vascular cell adhesion molecule: implications for its mode of action in multiple sclerosis. Journal of Neuroimmunology 161:169-176, 2005.

Allie R, Hu L, Mullen K, Dhib-Jalbut S, Calabresi PA. Bystander modulation of

chemokine receptor expression on peripheral blood T lymphocytes mediated by Glatiramer therapy. Arch Neurol 62:889-894, 2005.

Presentations Makar TK, Trisler D, Bever CT, Dhib-Jalbut S. Delayed onset and susceptibility to

experimental allergic encephalomyelitis (EAE) by interferon-ß (IFNß) gene therapy in mice. Society for Neuroscience meeting, Oct 23, 2004, Washington DC.

Session Chair, Americas Committees for Treatment and Research in MS (ACTRIMS). Toronto, October 2, 2004.

Session Chair, Neuroimmunology, American Academy of Neurology 57th Annual meeting, Miami, Florida, April 14, 2005.

Symposium organizer and Chair. Neuroprotective strategies in multiple sclerosis. Princeton, NJ. May 21, 2005.

Symposium Chair and speaker. Clinical Strategies in MS: Effectively Treating a Long-term Disease. Organized by the postgraduate Institute for Medicine. Orlando, Florida. June 3, 2005.

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Honors National Multiple Sclerosis Mid-Jersey Chapter Volunteer Award of the year National Multiple Sclerosis Mid-Jersey Chapter Board of Trustees Service / Administrative Committees 2004-Current Chair; University Medical Group (UMG) Finance Committee, Robert Wood

Johnson Medical School (RWJMS) 2004 Chair, Department of Physiology Review Committee 2004-Current University Medical Group-RWJ Strategic Planning Committee 2003-Current University Medical Group Board of Governors, RWJMS 2003-Current University Medical Group Operation Committee, RWJMS 2003-Current University Medical Group Executive Committee, RWJMS 2003-Current RWJUH Medical Board 2003-Current Board of Directors Professional Affairs Committee 2004-Current Task Force on Education Committee-RWJMS 2004-Current Board Member, Neuroscience Product Line, Robert Wood Johnson

Medical School

Editing/Consulting Associate Editor, Journal of Neuroimmunology Christoper G. Janson, M.D. Dr. Janson continues to have an active role in Gene Therapy for Canavan Disease, a Phase I/II clinical study sponsored through NIH with UMDNJ-RWJ and Cooper Hospital. He is currently collaborating with researchers at the University of Minnesota on Gene Therapy for Alzheimer's, while pursuing further neurosurgical training there. In addition, he has become very involved in ethical & legal issues surrounding gene patents and recently published in Nature Reviews Genetics on this topic with additional papers forthcoming in the gene therapy literature. He has published several recent papers on non-gene therapy approaches to Canavan disease as well as a forthcoming accepted paper on the natural history of the disease.

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Edmund C. Lattime, Ph.D. Research Activities Dr. Lattime¹s research focuses on the development of rationally designed immunotherapeutic strategies for the therapy of solid tumors. In particular, his laboratory focuses on modulating the tumor-host interface through the use of vaccines as well as local gene transfer with the goal of manipulating basic immune mechanisms towards the development of systemic cell-mediated antitumor immune responses. Through the use of murine models, Dr. Lattime’s lab in the last year has furthered his studies into major mechanisms of tumor escape from immune recognition (cytokine-mediated suppression of dendritic cell function) and developed a series of new gene based therapeutics for evaluation. Clinically, his laboratory has developed a protocol which was approved and funded by the NCI Cancer Therapeutics Evaluation Program (CTEP) involving the use of recombinant poxvirus given into the bladder in patients prior to cystectomy. In its first 6 mos., the trial accrued 6 pts and is continuing to accrue. This is an interdisciplinary project involving members of the Department of Surgery, the Department of Medicine, The Department of Pathology, and the School of Public Health. Teaching RWJMS Hem Onc Fellows lecture: “Tumor Immunology” UMDNJ-Rutgers MD/PhD Molecular Medicine Seminar

October 4, 2004 January 26, 2005 UMDNJ-Rutgers GSBS Course “Introduction to Molecular Medicine”

(MICR-6003) lecture “Gene Therapy for Cancer and Non-Cancer Conditions” January 26, 2005

UMDNJ-Rutgers Course “Current Concepts of Immunology (MICR-6005) lectures: “Tumor Immunology” 3/9/05 “Vaccine Development” 3/16/05 Student research projects supervised: Emmanuel Gabriel, MD/PhD Student “ Regulation of Immunity to Tumors: Elucidating

Tumor-Escape Mechanisms” Partha Ray, M.D. Surgical Resident “Anti-Her2 Tumor Immunity in a Mouse Model” Amal Mansour, M.D., Ph.D. Postdoctoral Fellow “Immunological effects of Intravesical

Gene Therapy in Patients with Bladder Cancer” Presentations Eastern Cooperative Oncology Group: Organized and Chaired Symposium

“Immunotherapy of Prostate Cancer” Dr. Lattime planned and chaired the Second Annual New Jersey Governor’s

Conference on Effective Partnering in Cancer Research. The meeting was

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attended by national leaders in translational research from the NIH, NCI, FDA etc. and included a keynote address from Governor James McGreevey.

Publications Lattime, E.C., Weiss, R.E., Stein, M.N., Wojtowicz, M., Todd, M.B., Morton, R.A.,

Hwang, J., Bancila, E., Ben-Menachem, T. and DiPaola, R.S. Phase I study of intravesical recombinant fowlpox-GM-CSF (rF-GMCSF) and/or recombinant Fowlpox-TRICOM (rF-TRICOM) in patients with advanced bladder cancer. J. Clin. Oncol. 23: 441s, 2005.

Submitted United States Patents Neutralization of immune suppressive factors for the immunotherapy of cancer Inventers: Edmund Lattime and Claude Monken Patent Application Number: 10/138,783. Service / Administrative Committees Government and Agency Review Committees: 2003 – 2005 NCI Biological Resources Branch Oversight Committee 2004 – present National Cancer Institute Study Section Cancer Immunopathology and Immunotherapy, (ad hoc) 2005 NCI Cancer Centers Review (ad hoc) Cooperative Group Involvement: (Eastern Cooperative Oncology Group, ECOG) 2003 – present Vice Chair, Pathology and Laboratory Sciences Committee 2003 – present Cochair, Developmental Therapeutics Committee Cancer Institute of New Jersey

Associate Director for Education and Training Member, Scientific Council Co-Leader, Cytokines, Cytokine Signaling and Cancer Program Faculty Director, Laboratory Services CORE Cochair, Scientific Review Board Member, Executive Committee Member, Human Research Oversight Committee Member, University Medical Center at Princeton Cancer Committee

UMDNJ-RWJMS Activities

Member, M.D./Ph.D. Admissions Committee Steering Committee, Minority training program

Department of Surgery

Chairman, Education Task Force Mentoring Process

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Director, Surgical Oncology Research Member, Appointments and Promotions Committee

Editing, Consulting Editor, Gene Therapy Issue, Seminars in Oncology 2005 Editorial Boards and Activities: 1996 - present Associate Editor, Cancer Research 1996 - present Abstract Reviewer, Am Assn. Cancer Research 2005 – present Editorial Board, Journal Clinical Oncology Academic Advisory Panels 2001 – present: Cleveland Clinic, Genitourinary SPORE program, Scientific advisor 2001 – present: University of Iowa, VAMC REAP Program Scientific Advisor Pharmaceutical Industry Relations Scientific Advisory Board, Jennerex Biologics Paola Leone, Ph.D. Research Activities Dr. Leone is currently the principal investigator of the first NINDS-sponsored clinical gene therapy Phase I study for Gene Therapy of Canavan Disease (CD) using AAV vectors. In addition to conducting a clinical research study on CD, Dr. Leone’s laboratory conducts basic research projects that directly study CD, a disorder that has been a focus of her research for nearly a decade. Dr. Leone is studying & characterizing the Canavan rat model for CD “tremor rat”. These studies run in parallel with the characterization of oligodendrocytes developments in the human brain. Furthermore Dr. Leone’s laboratory is also studying the effect of common and novel CD genetic mutations on development and characterizing of altered genes and pathways in CD. She is also conducting a research project designed to generate pre-clinical data for a cell-based therapy for CD and other white matter disorders. Teaching Medical Physiology, Pulmonary PCP Case Conference.

Member of the judging committee for the Resident's Research week and poster contest

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Publications Inoue, H., Osawa, I. , Murakami, T., Kimura, A., Hakamata Y., Sato, Y., Kaneko,T.,

Okada, T., Ozawa, K., Francis J., Leone, P., and Kobayashi, E. (2005) Development of Inbred Transgenic Strains of Rats with LacZ or GFP. Biochemical & Biophysical Research Communication. 329(1): 288-95.

Assadi, M., Janson, C.G., Bilaniuk, L., Shera D., Leone, P. (2005) Case Report: Lithium Citrate for Canavan Disease. Pediatric Neurology. 33:235-243.

Tavazzi, B., Lazzarino, G., Amorini, A.M., Bellia, F., Fazzina, G., Giardinia, B., Leone, P. (2005) Sensitive and reproducible high performance liquid chromatographic separation of N-Acetyl Aspartate, N-Acetyl Glutamate and N-Acetyl-Aspartyl Glutamate suitable for the biochemical evaluation of Canavan Disease patients. Clinical Biochemistry. 38(11):997-1008

Presentation Leone., P. McPhee, S.W.J., Janson,C.G., Samulski J., Wang D.J., Bilaniuk L. (2005)

Gene Therapy Case Study Report. National Tay Sachs & Allied Disorders, New Orleans, LA.

Leone, P., McPhee, S.W.J., Janson,C.G., Samulski J., Goldfarb, O., Saslow, E., Goldman, H.W., Wang D.J., Bilaniuk L. (2005). Safety and Efficacy of AAV-mediated Gene Transfer for Canavan Disease. American Society of Gene Therapy. Symposium - Clinical Trials: Metabolic Disorders, St Louis, MI.

Leone, P., McPhee, S.W.J., Janson,C.G., Samulski J., Goldfarb, O., Saslow, E., Goldman, H.W., Wang D.J., Bilaniuk L. (2005). Cell and Gene Based Experimental Therapies for White Matter Diseases. Pharmaness Symposium, Pula, Italy.

Honors Woman 2006 Lioness Club, Italy Editing/Consulting

Books: Zeng, B-J., Pastores, G., Leone, P., Raghavan, S., Wang, Z-H., Ribeiro, L.A., Torres, P.,

Ong, E., Kolodny E. (2005) Mutation Analysis of the Aspartacylase Gene in Non-Jewish Patients with Canavan Disease. N-Acetylaspartate, Series: Advances in Experimental Medicine and Biology, Vol 576. Springer, 2006.

Editor: Janson CG, Leone P, Simeone F, Freese AM, Eds. Molecular Neurosurgery (Progress in

Neurosurgery,Volume #17), Karger, Basel, 2005

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Mei-Ling Li, Ph.D. Research Activities Development of an in vitro system for the synthesis of Sindbis virus (SV) SG RNA. Teaching Mentoring an undergraduate student to study the fidelity of SV polymerase. Publications Mei-Ling Li, Yen-Huei Lin,, H. Anne Simmonds, and Victor Stollar (2004). A Mutant of

Sindbis Virus Which Is Able To Replicate in Cells with Reduced CTP Makes a Replicase/Transcriptase with a Decreased Km for CTP. J Virol. 78(18):9645-51.

Shin-Ru Shih, Victor Stollar, Jing-Yi Lin, Shih-Cheng Chang, Guang-Wu Chen, and Mei-Ling Li (2004). Identification of genes involved in the host response to enterovirus 71 infection. J Neurovirol. 10(5): 293-304.

Shih-Cheng Chang, Jing-Yi Lin, Lily Yen-Cheng Lo, Mei-Ling Li, and Shin-Ru Shih (2004). Diverse apoptotic pathways in enteroviruses 71-infected cells. J. Neurovirol. 10(6): 338-349.

Randall D. McKinnon Ph.D. Research Funding

Source: New Jersey Commission Spinal Cord Research Title: Netrin directed glial migration Dates: 06/15/05 -06/30/07 PI: R.D. McKinnon, 50% effort Direct/indirect/total Costs: $ 360,690

Source: The Foundation of UMDNJ Title: "Netrin signaling in oligodendrocytes" Dates: 07/04-06/05 PI: R.D. McKinnon

Direct/indirect/total Costs: $ 25,000

Source: NIH #2RO1 MH54652-09 Title: "PDGF Signaling in oligodendrocyte development" Dates: 05/01/05 -04/30/06 PI: R.D. McKinnon Direct/indirect/total Costs: $1,125,000; $622,743; $1,747,743

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Source: Cook College Scholarship (Brandy Houser, Rutgers ‘05) Title: “Myelination in co-cultures from pdgfra-mutant mice” Source: RWJMS Neuroscience Summer Studentship (Alan Gordon, Brown U. ‘06) Title: “Netrin directed glial migration in Drosophila embryogenesis” Source: Neuroscience Summer Studentship (Mirat Shah, MIT ‘08) Title: “Gliogenesis in Drosophila” Teaching Molecular Medicine Seminar, Fall 2004

Molecular Biosciences Advanced Topics, Spring 2005 Publications

R.D. McKinnon, S. Waldron and M.E. Kiel (2005). PDGF -Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3'-Kinase and Phospholipase C Pathways during Oligodendrocyte Maturation. J .Neuroscience 25(14): 3499-3508.

Labrador, J.P., D. O’Keefe, S .Yoshikawa, R.D. McKinnon, J.B. Thomas and G. Bashaw (2005). The homeobox transcription factor even-skipped regulates Netrin-receptor expression to control dorsal motor-axon projections in Drosophila. Current Biol. 15(15):1413-1419.

Abstracts and Posters (published/presented): Alan Chang, M. Kiel, D. O’Keefe, S. Yoshikawa, J.B. Thomas and R.D. McKinnon

(2004). Control of glial position via the repulsive netrin receptor Unc5. CSH Axon Guidance & Neural Plasticity, Cold Spring Harbor NY.

Brandy L. Houser, M.E. Kiel and R.D. McKinnon (2004). Growth Factors for CNS Repair: The Role of PDGF α-Receptor in Migration of Glial Progenitor Cells. Foreign Research Exchange Program, San Palo Brazil.

Alan Chang, Alan Gordon, M.E. Kiel and R.D. McKinnon (2004). The netrin receptor UNC5 directs migration of glial progenitor cells in the CNS. Inaugural Symposium on Stem Cell Research in NJ, New Brunswick NJ.

R.D. McKinnon, Alan Chang and M.E. Kiel and (2004). Candidate genes for neural stem-progenitor cell maturation identified by RDA. Inaugural Symposium on Stem Cell Research in NJ, New Brunswick NJ.

Brandy L. Houser, M.E. Kiel and R.D. McKinnon (2005). The role of PDGF α-receptor in migration of glial progenitor cells. Cook Scholars Symposium, New Brunswick NJ.

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Presentation EOSHI Seminar Series, Rutgers University, “The Detroit Code of neural development:

Growth Factors that brake, clutch, accelerate and steer” Honors Science Communication Poster Award, Rutgers Cook College Rutgers -San Palo Brazil Foreign Research Exchange Program Administrative Committees Departmental

Director, Neurosurgical Research Laboratory University

Member, Grant Review Panel, UMDNJ Foundation Grants Academic Standing Committee, Grad Program in Physiology Integrative Biology Curriculum Committee, Graduate Program in Physiology Integrative Biology

Editing/Consulting

Journal Editorial Boards J. Neuroscience, Mol. Cell. Neuroscience M. Maral Mouradian, M.D. Research Activities Dr. Mouradian’s research program continues to focus on the molecular underpinnings of Parkinson’s disease and related neurodegenerative disorders. Among her discoveries during this academic year was a novel mechanism of cytoprotective effect of a protein called DJ-1, which is encoded by a gene that is linked to recessively inherited Parkinson’s disease when mutated. Thus, loss function of DJ-1 results in activation of a death signaling pathway through the Daxx-ASK1 system. dr. Mouradian’s team found that DJ-1 binds to the death protein Daxx, sequesters in the nucleus and prevents it from gaining access to the cytoplasm, from activating ASK1 and therefore from catapulting cells down the death pathway. A disease associated mutant isoform of DJ-1 loses all these functions. Another line of investigations in Dr. Mouradian’s laboratory elucidated the importance of phosphorylation of another Parkinson associated gene product, alpha-synuclein, as well as its molecular partner synphilin-1 in regulating their interaction and forming intraneuronal inclusion bodies. Furthermore, her team demonstrated that these inclusions are cytoprotective rather than toxic.

Teaching

Physical Diagnosis course at RWJMS

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Publications

Junn, E., Taniguchi. H., Jeong, B.S., Zhao, X., Ichijo, H., Mouradian, M.M.: Interaction of DJ-1 with Daxx inhibits ASK1 activity and cell death. Proc. Natl. Acad. Sci. USA, 102(27): 9691-9696, 2005.

(This publication has been highlighted in the “THIS WEEK IN THE PNAS” section of the journal. It has also been highlighted in the Alzheimer Research form website.)

Bara-Jimenez W., Bibbiabi, F., Morris, M.J., Dimitrova, A., Sherzai, A., Mouradian, M.M., Chase, T.N.: Effects of serotonin 5HT1A agonist in advanced Parkinson’s disease. Mov. Disord., Epub 2005.

Bara-Jimenez W., Dimitrova , T., Sherzai, A., Favit, A., Mouradian, M.M., Chase, T.N.: Effects of monoamine reuptake inhibitor NS 23390 in advanced Parkinson’s disease. Mov. Disord., 19(10):1183-1186, 2004.

Tanaka, M., Kim, Y.M., Lee, G., Junn, E., Iwatsubo, T., Mouradian, M.M.: Aggresomes formed by α-synuclein and synphilin-1 are cytoprotective. J. Biol. Chem., 279(6):4625-4631, 2004.

Dhib-Jalbut, S., Mouradian, M.M.: Delivery of transgenically modified adult bone marrow cells to the rodent central nervous system. Expert Opin. Biol. Th., 4(5):669-675, 2004.

Lee, G., Tanaka, M., Park, K., Lee, S.S., Kim, Y.M., Junn, E., Lee, S.H., Mouradian, M.M.: Casein kinase II mediated phosphorylation regulates α-synuclein / synphilin-1 interaction and inclusion body formation. J. Biol. Chem., 279(8):6834-6839, 2004.

Mouradian, M.M.: Should levodopa be infused into the duodenum? Neurology, 64(2):182-183, 2005.

Presentations Junn, E., Taniguchi, H., Zhao, X., Mouradian, M.M: Protection of cell death by DJ-1.

Soc. Neurosci. Abstr., Vol 29, Program No. 558.3, 2004. (Principal Author) Presented a poster at the 6th annual Research Day of the Robert Wood Johnson

Medical School on November 15th entitled “Protection of cell Death by DJ-1” (Principal Author)

Spotlight on Parkinson’s Disease, Confronting Issues and Opportunities in Management, co-sponsored by the UMDNJ Center for Continuing and Outreach Education. Type of participation: CME Activity Director

Neuroprotective Strategies for Multiple Sclerosis, co-sponsored by the UMDNJ Center for Continuing and Outreach Education. Held in Princeton, New Jersey

Type of participation: Speaker, topic “Molecular Genetics of Parkinson’s Disease and New Therapeutic Targets”

Delivered an invited lecture at the University of Pennsylvania on March 24, 2005 entitled: “Molecular Pathogenesis of Parkinson’s Disease.”

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Delivered a lecture entitled “Molecular pathogenesis of Parkinson’s disease and emerging therapeutic targets “ at the International Symposium on Aging and Neurodegeneration sponsored by the Age-Related and Brain Diseases Research Institute of Kyung Hee University in Seoul, South Korea, on April 18, 2005.

Gave a lecture entitled “Molecular Pathogenesis of Parkinson’s Disease and Emerging Therapeutic Targets” at the Graduate Program in Biochemistry and Molecular Biology at RWJMS in December 2004. This was part of a seminar series called “Progress in Understanding Human Neurodegenerative Diseases.”

Delivered an invited lecture entitled “The Rationale for Continuous Dopaminergic Stimulation in Parkinson’s Disease” at a satellite symposium of the 16th International Congress on Parkinson’s Disease and Related Disorders in Berlin, on June 6, 2005.

Chaired a session entitled “Movement Disorders – Genetics, Pathophysiology and Epidemiology” at the Annual Meeting of the American Academy of Neurology in Miami Beach, Florida, on April 13, 2005

Presented the progress report of the UMDNJ-Robert Wood Johnson Medical School’s Advanced Center for Parkinson Research at the American Parkinson Disease Association’s Annual meeting, May 7, 2005.

Service Presented the report of the Scientific Advisory Board of the American Parkinson

Disease Association to the Association’s annual Board of Directors’ meeting in Newark, NJ in November 2004.

Granted a live interview on CNN International about the use of embryonic stem cells in

research. In the debate format, Dr. Mouradian argued in support of such research. Date: May 24, 2005.

Administrative Committees Departmental

Appointment and Promotion Committee, Department of Neurology, RWJMS

RWJMS Awards Nomination Committee member Space Advisory Committee, UMDNJ-RWJMS Website Designing Committee, UMDNJ-RWJMS

Editing/Consulting

Journal Editorial Boards Member, Scientific Advisory Board, American Parkinson Disease Association: This

service involves reviewing applications for research grants and advanced centers of excellence. In addition, we meet annually to discuss these

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applications and to set the priorities and policies of the Board. Associate Editor, Pharmacology and Therapeutics: I cover the area of neurological

diseases, with an emphasis on neurodegenerative and neuroimmunologic disorders.

Editorial Board Member, Neurology: this is the most widely circulated journal in the

field of neurology. Margaret Prescott, Ph.D. Research Activities Clinical Research in Gender Aspects of Cardiovascular Disease and Biomarkers of Cardiovascular Disease Teaching Appointed Guest Professor, Charité - Universitätsmedizin Berlin (Charité Medical

University in Berlin) There I taught in three graduate programs

1) Clinical Research Center Graduate Program 2) Gender Institute of Medicine Graduate Program 3) Master Study Program in Health and Society

Publications Articles

Erkens, J.A., Pannerman, M.M., Klungel O.H., Prescott, M.F., Herings, R.M. Differences in antihypertensive drug persistence associated with drug class and gender. Pharmacoepidemiol Drug Safety 14: 795-803, 2005

Majahalme S.K., Baruch L., Aknay N., Goedel-Meinen L., Hofmann M., Hester A., Prescott M.F., and the Val-HeFT Study Investigators, Comparison of treatment benefit and outcome in women versus men with chronic heart failure (from the Valsartan Heart Failure Trial). Am J Cardiol. 95: 529-32, 2005.

Abstracts

Majahalme S.K., Baruch L., Aknay N., Goedel-Meinen L., Hofmann M., Hester A., Prescott M.F., Treatment benefit and outcome in women versus men with chronic heart failure, Circulation 110: IV-435, 2004.

Nussberger J, Gradman AH, Schmieder RE, Lins RL, White WB, Prescott M, Changes

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in plasma renin match the antihypertensive effects of aliskiren in patients with hypertension: placebo/irbesartan-controlled trial with the orally active renin inhibitor aliskiren. Am J Hypertens 2005;18:234A, P624

Presentations American Heart Association Go Red for Women, San Diego, Feb. 2005 (keynote

speaker) "Gender Aspects of Stroke" International Society of Hypertension, Sao Paulo, Brazil, July 2004 "Influence of Obesity

versus Blood Pressure on Biomakers of Inflammaiton, Oxidaiton and Thrombosis"

Editing/Consulting Peer reviewer for: Circulation, Arteriosclerosis Thrombosis and Vascular Biology Karel Raska, M.D. Research Activities Ongoing research on the prognostic factors and survival in breast carcinoma. Correlation of molecular probes for human papilloma virus and pathologic changes in “liquid” cervical cytology preparations and biopsy specimens. Teaching Elective course in Surgical Pathology for 4th year medical students Laboratory Medicine elective for residents in Medicine and in Obstetrics and

Gynecology

Presentation World Congress of the Society for Arts and Sciences in America, July 2004, Olomouc,

Czech Republic; Plenary Lecture: Vše co jsem prožil, źil jsem rád: Four decades in American Academic Medicine.

Honors Honorary professor, 3rd Medical Faculty, Charles University, Prague

Service Chairman, Department of Laboratory Medicine and Pathology, Saint Peter’s University

Hospital

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Director, Division of Laboratory Medicine, SPUH Director of the Blood Bank, SPUH Director Institute for Molecular Diagnostics and Pathology, SPUH Administrative Committees Executive Council, RWJMS Internal Advisory Board, CINJ Chairman, Performance Improvement Committee, SPUH Executive Committee of the Medical Staff, SPUH Vice President, Society for Arts and Sciences in America, Bethesda, MD Scientific Council, Third Medical Faculty, Charles University, Prague, Czech Republic Editing/Consulting Editorial Board: Clinical Therapeutics Michael Reiss, M.D. Research Activities Mechanisms of resistance of squamous cancer cells to inhibition of growth by

Transforming Growth Factor-ß. Mechanisms of resistance of breast cancer cells to inhibition of growth by Transforming

Growth Factor-ß. Development of selective TGFß receptor kinase antagonists as novel anti-cancer and

anti-fibrotic agents Development of a Tissue Microarray Shared Resource of the Cancer Institute of New

Jersey

Teaching “Genomics in Cancer Therapeutics”

Publications Ge R, Rajeev V, Subramanian G, Reiss KA, Liu D, Higgins L, Joly A, Dugar S, Chakravarty

J, Henson M, McEnroe G, Schreiner G and Reiss M, Selective Inhibitors of Transforming Growth Factor-b type I Receptor Kinase Block Cellular Transforming Growth Factor-b Signaling. Biochem. Pharmacol. 68:41-50, 2004.

Chen W, Reiss M and Foran DJ, A prototype for unsupervised analysis of tissue microarrays for cancer research and diagnostics. IEEE Trans Inf Technol Biomed 8: 89-96, 2004.

G. Subramanian, R. E. Schwarz, L. Higgins, G. McEnroe, S. Chakravarty, S. Dugar, and

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M. Reiss. Targeting endogenous Transforming Growth Factor-ß receptor signaling in smad4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype. Cancer Res. 64:5200-5211, 2004

Uemura M, Swenson ES, Gaca MD, Giordano FJ, Reiss M, Wells RG. Smad2 and Smad3 Play Different Roles in Rat Hepatic Stellate Cell Function and {alpha}-Smooth Muscle Actin Organization. Mol Biol Cell 2005.

Abstracts, letters: Kareddula, A, Selvanayagam, EZ, Reiss, M. Endogenous transforming growth factor-ß-

regulated gene expression profile in human epidermal keratinocytes is dependent on level of receptor kinase activity. Proc Amer Assoc Cancer Res 46:1276, 2005.

Ge, R.,Rajeev, V., Ray, P., Lattime, E., Rittling, S., Medicherla, S., Protter, A., Murphy, A., Chakravarty, J., Dugar, S., Schreiner, G., Barnard, N., and Reiss, M. Inhibition of mouse mammary tumor growth and metastasis by selective transforming growth factor-β type I receptor kinase blockade. Proc Amer Assoc Cancer Res. 46:604, 2005

Xie, W., Liu, F., Reiss, M. Depression of smad effectors of transforming growth factor-ß signaling is associated with breast cancer progression. Proc Amer Assoc Cancer Res. 46:738-739, 2005

Bharathy, S., Reiss, M. Activation of ras or myc genes in keratinocytes is insufficient to overcome Transforming Growth Factor-β-mediated growth suppression. Proc Amer Assoc Cancer Res. 46:, 2005

Subramanian, G., Reiss, M. Differential activation of receptor-associated SMADS may mediate Transforming Growth Factor-βs oncogenic effects on human pancreatic cancer cells. Proc Amer Assoc Cancer Res. 46:, 2005

Presentations “TGFß and Cancer: Surprises at Every Turn” Surgery Grand Rounds. Robert Wood

Johnson Medical School. New Brunswick, NJ. October 27, 2004 “Dissecting and Analyzing TGFß Signaling: Surprises at Every Turn” Grand Rounds-

Division of Pathology & Laboratory Medicine. University of Texas M.D. Anderson Cancer Center , Houston, TX. October 29, 2004.

“Dissecting and Targeting TGFß Pathway: Surprises at Every Turn” Invited Seminar. Scios, Inc., Freemont, CA. January 24, 2005

“Dissecting and Targeting TGFß Pathway: Surprises at Every Turn” Invited Seminar. Pfizer, Inc., Groton, CT. March 11, 2005

Service Attending

Inpatient: December 2004, May 2005 Outpatient Weekly CINJ Breast Center as of June 7, 2001 Consult service: December 2004, May 2005

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Affiliated hospital program:

Administrative Committees National

Member, Cancer Research Manpower Review Committee, National Cancer Institute, National Institutes of Health.

Member, Pathobiology-1 Study Section, Department of Defense Breast Cancer Research Program

Reviewer, Netherlands Cancer Foundation research grants Member, Tumor Microenvironment Study Section, National Cancer Institute,

National Institutes of Health University:

Associate Director for Translational Research, The Cancer Institute of New Jersey Director, Breast Cancer Research Program, The Cancer Institute of New Jersey

Editing/Consulting Editor: “Oncology Research-An International Journal”

Associate Editor: “Cancer Research” and “Clinical Cancer Research”

Reviewer: Cancer Research, Cell Growth & Differentiation; Oncology Research, Eur. J. Cancer Clin. Oncology, J. Cellular Physiology, Genomics, Lab. Investigation, J. Cellular Biochem., Clinical Clinical Cancer Research, J. Pathology, New England Journal of Medicine

Hugh Rosen, Ph.D. Research Activities Studies on receptor regulation of lymphocyte egress and pulmonary barrier function. Chair, The Molecular Libraries Screening Center Network Steering Group of the NIH

Date Time Institution Meeting 7/16/04 7:30AM CSM Tumor Board 8/6/04 8:00AM SMC Tumor Board

9/15/2004 8:00AM RWJ-Hamilton Cancer Committee 10/8/04 8:00AM MCP Tumor Board 11/17/04 8:00AM RWJ-Hamilton Cancer Committee 12/17/04 12:00PM RBMC Tumor Board 2/23/05 8:00AM SOCH Tumor Board 7/12/05 12:00PM JFK Medical Center Tumor Board

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Roadmap. Publications

Wei SH, Rosen H, Matheu MP, Sanna MG, Wang SK, Jo E, Wong CH, Parker I, Cahalan MD Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat. Immunol. 6, 1228-1235 (2005).

Rosen, H. & Goetzl, E. J. Sphingosine 1-phosphate and its receptors: An autocrine and paracrine network. Nat Rev Immunol 5, 560-570 (2005).

Rosen, H. Chemical approaches to the lysophospholipid receptors. Prostaglandins & other Lipid Mediators 77, 179-84 (2005).

Martinez X, Kreuwel HT, Redmond WL, Trenney R, Hunter K, Rosen H, Sarvetnick N, Wicker LS, Sherman LA. CD8+ T Cell Tolerance in Nonobese Diabetic Mice Is Restored by Insulin-Dependent Diabetes Resistance Alleles. J. Immunol. 175, 1677-85 (2005).

Jo E, Sanna MG, Gonzalez-Cabrera PJ, Thangada S, Tigyi G, Osborne DA, Hla T, Parrill AL, Rosen H. S1P1-Selective In Vivo-Active Agonists from High-Throughput Screening: Off-the-Shelf Chemical Probes of Receptor Interactions, Signaling, and Fate. Chemistry & Biology 12, 703-715 (2005).

Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L, Lin WY, Hu Z, Lu Y, Chen Y, Wu Y, Meng YG, Gribling P, Lin Z, Nguyen K, Tran T, Zhang Y, Rosen H, Martin F, Chan AC Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. Journal of Immunology 174, 817-826 (2005).

Gon Y, Wood MR, Kiosses WB, Jo E, Sanna MG, Chun J, Rosen H.. S1P3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF. PNAS 102, 9270-5 (2005).

Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H. Sphingosine 1-phosphate (S1P) receptor subtypes S1P(1) and S1P(3), respectively, regulate lymphocyte recirculation and heart rate. Journal of Biological Chemistry 279, 13839-13848 (2004).

Goetzl, E. J. & Rosen, H. Regulation of immunity by lysosphingolipids and their G protein - coupled receptors. Journal of Clinical Investigation 114, 1531-1537 (2004).

Presentation

Keystone lymphocyte trafficking 2005 FASEB meeting lysophospholipids 2005 ASBMB Lipid Theme 2005 AAI Advanced Course 2005 9th International Eicosanoid Japan Society Immunology

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University of Tokyo University of Washington Johns Hopkins University of California Irvine

Srijata Sarkar, Ph.D. Research Activities Regulation of cytokine gene expression by mRNA turnover Cytokine expression by cells of the immune system plays a crucial role in the regulation of immune responses. Expression of many cytokines in response to external stimuli during an immune response is regulated by transcription as well as posttranscrptional events. A major posttranscriptional mechanism for regulating the level of gene expression of many cytokines, protooncogenes and growth factor mRNAs is through the control of mRNA turnover. The rapid turnover of mRNAs is determined in part by the A+U-rich elements in the 3'-untranslated region. The overall goal of this project is to understand the mechanisms of regulation of expression of cytokines involved in inflammation such as proinflammatory IFN-γ and anti-inflammatory IL-10. These cytokines have opposing effects and they antagonize each other’s production and functions.

Our previous studies have indicated that the increased expression of IL-10 in human melanoma tumor cell MNT-1 as compared to its normal counterpart is in part due to increased stability of the IL-10 mRNA. Examination of the 3'-untranslated region of IL-10 mRNA revealed the presence of multiple AU-rich elements (ARE) that might target the mRNA for rapid turnover. The cytoplasmic extract from MNT-1 cells has significantly lower ARE-binding activity compared to that of normal melanocytes. One of the major ARE-binding activities in normal melanocytes was identified as AUF1, an RNA destabilizing protein. In MNT-1 cells, AUF1 appears to be restricted to the nuclear fraction. A reduced cytoplasmic level of AUF1 in melanoma cells appears to be responsible for IL-10 overexpression with deleterious consequences for tumor surveillance and rejection. Nuclear sequestration of AUF1 appears to be a novel mechanism, which can be used by tumor cells to alter the regulation of mRNA turnover. At present we are investigating the role of mRNA turnover in the regulation of IL-10 and IL-10 receptor in response to inflammatory stimuli. IL-10 is expressed at a low level in T- and B-lymphocytes, monocytes, macrophages, keratinocytes and many tumors. We have used THP-1, a human monocytic leukemia cell line, as a model to examine whether the expression of IL-10 and IL-10 receptor chains are modulated in response to external stimuli such as bacterial LPS and IFN-γ. THP-1 cells, like primary monocytes are known to induce a host of inflammatory cytokines in response to appropriate stimuli. We have demonstrated that LPS stabilizes mRNAs encoding IL-10 and IL-10 receptor sub-unit 1 (IL-10R1). IFN-γ opposes LPS-mediated stabilization of IL-10 mRNA while it increases LPS-mediated stabilization of IL-10R1. The sequence

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analysis of the 3'-UTR of human IL-10 and IL-10R1 mRNA revealed the existence of multiple AUUUA pentamers. These ARE sequences destabilize IL-10 and IL-10R1 mRNA and contribute to the maintenance of a low level of IL-10 and IL-10R1 in unstimulated cells. We are investigating the role of the 3’-UTR in the regulation of stimulus-dependent (LPS and IFN-γ changes) IL-10 and IL-10R1 expression.

Determining the mechanisms by which the expression of these cytokines is regulated will be useful in both understanding the complexity of the immune system and the interrelationships of these important cytokines. Furthermore, understanding the role of mRNA turnover in the regulation of the immune system will provide an opportunity to develop new therapeutics to control these processes and treat a variety of diseases such as rheumatoid arthritis and other immune disorders. Lee Ann Schein, Ph. D. Research Activities As the Director of the DNA Core Facility, I am responsible for overseeing, hiring, and training personnel; assisting in grant submissions; supervising billing; setting pricing policies; and aiding users to troubleshoot problems. During this past year, the lab has spent a great deal of time optimizing conditions for several new applications. We have been working with end users in piloting experiments using STRP (Simple Tandem Repeat Polymorphisms) analysis. We worked out the conditions for the studies on the ABI 3100 DNA Sequencer using florescent primers. This technique has been very successful in the genotyping of large amounts of samples effortlessly and rapidly. In addition, the Core has acquired a quantitative real-time PCR analysis system complete with robotics. The lab staff has been working with users to initiate applications utilizing the system. The DNA Synthesis and Sequencing Core Facility has expanded, becoming increasingly more streamlined, and incorporating state-of-the-art technology. Oligonucleotide synthesis usage has also increased as well as becoming more efficient. Lastly, I was asked to participate in the UMDNJ Bioterrorism Curriculum Consensus Conference (BTC3). This was a daylong conference to develop a set of bioterrorism/public health emergency preparedness learning objectives the UMDNJ clinical health professional schools. It also involved several follow up sessions to review the reports via email. Laboratory Support Staff Regina Felders-Gibbions, Technician

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Sheila Mazar, Technician John Spychala, PhD, Technician Beverly Novembre, Accounts Clerk Owolabi Shonuga, Undergraduate Rori Hodges, Undergraduate Dhenu Solanki, Undergraduate Irene Khakula, Undergraduate Neal Mohandas, Undergraduate Nivea Panchalingam, Undergraduate Stathis Theodoropoulos, Undergraduate Deborah Yawson, Undergraduate Trishna Nath, Undergraduate Ronald Udasin, Undergraduate

Teaching Microbiology and Immunology MGMB 6000, Assistant to the Course Director Review sessions for the UMDNJ-RWJMS Cognitive Skills Program in Microbiology Microbial Organisms UMDNJ-RWJMS Physician Assistant Program (02:745:209)

Participated in the Rutgers Introduction to Molecular Biology and Biochemistry Research 315 Course (March) and in the Waksman Student Scholars Program (summer), giving an introductory lecture on DNA sequencing to the students in the classes and guiding the laboratory instructors on sample preparation. The DNA Core Facility then sequenced the students’ DNA samples. Supervised and taught 10 Rutgers work-study students and/or student assistants in my laboratory:

Owolabi Shonuga Rori Hodges Dhenu Solanki Irene Khakula Neal Mohandas

Nivea Panchalingam Stathis Theodoropoulos Deborah Yawson Trishna Nath Ronald Udasin

Presentations Presented the poster session for the DNA Sequencing Shared Resource for CINJ’s

CCSG site visit in May of 2004. Participated in UMDNJ Bioterrorism Curriculum Consensus Conference (BTC3)

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Seminars Sponsored JV Vandergrift; Real-Time PCR Symposium; 9/22/04

Talks include: “Introduction to Sequence Detection and a

ABI Prism 7900HT Capabilities” “SNP Genotyping and Gene Expression Assay Design Options” “Methods of Real-Time PCR Quantitation” “SNP Genotyping and Gene Expression Taqman Assays work Flows”

Laura Sailor; “Expression Arrest – shRNA Library for Mammalian Cells: The Hannon-Elledge Collection “ 2/8/05

Applied Biosystems Gene Expression Symposium 5/9/05 Talks include:

“Molecular characterization of Early Stage Breast Carcinoma Using Applied Biosystems Gene Expression Tools”

“Quantitative Gene Expression Analysis: From Discovery to Practice” “Validation of Gene Expression with Applied Biosystems Real-Time PCR

Systems” Administrative Committees Departmental Core Facilities Committee UMDNJ-RWJMS UMDNJ-RWJMS Summer Biomedical Careers Program University/Campus Co - Resource Manager, Cancer Institute of New Jersey Resource Manager, National Institute of Environmental Health Sciences Center Member Of The CINJ DNA Core Facility Committee Member Of CINJ Microarray Shared Resource Advisory Committee Community/state service Taught 2 hour lecture on DNA to the elementary school children in grade 7 of Yeshiva

Shaarei Tzion, 51 Park Avenue, Piscataway, NJ CORE FACILITIES DNA Sequencing and Synthesis Core Facility The DNA Synthesis and Sequencing Core Facility of the Department of Molecular Genetics and Microbiology serves as a shared resource for the Cancer Institute of New Jersey (CINJ) and The National Institute of Environmental Health Sciences (NIEHS) Center at the Environmental and Occupational Health Sciences Institute (EOHSI) Center of Excellence. The overall purpose of this shared resource is to provide a

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centralized, high quality, cost-effective facility for DNA sequencing and synthesis for use by the entire scientific community at RWJMS and Rutgers University. Automated fluorescent sequencing provides much more data (generally 400 to 850 nucleotides) from a single loading than can be achieved by manual sequencing methods most researchers previously performed in their laboratories. The cost of such a system is prohibitively high, thus only a shared resource such as the DNA laboratory can maintain and operate this system efficiently. The facility runs two state of the art ABI 3100 capillary sequencers with a capacity of two 96 well plates per machine. For DNA Sequencing, CINJ and NIEHS members pay $8 per sequence with 400 bases of sequence guaranteed; this rate is 20% less than charged to other academic users ($10). User fees are designed to defray reagent costs and operating expenses, while ensuring members access to a state-of-the-art facility at low cost. The high throughput of the DNA sequencer and the use of three trained staff members for DNA sequencing now results in a typical turnaround time of 1 day for most sequencing. Thus, researchers are freed from performing these critical support experiments for their work, and can focus on the application of these technologies to addressing the important questions in their research programs. By providing synthetic oligonucleotides to all members of the University, many studies are greatly facilitated at significant cost discounts over what individual laboratories could obtain. The DNA Synthesis pricing policy reflects a significant discount on the list prices from IDT, the commercial provider of the service, based on the bulk orders placed by the facility.

The DNA synthesis and sequencing facility serves our entire scientific community at RWJMS and Rutgers University. This is an example where our Departmental resources have been used to develop a core facility that is essential for the scientific development of RWJMS. Leonard H. Sigal, MD Research Activities Dr. Sigal is a Director in Immunology at the Pharmaceutical Research Institute of Bristol-Myers Squibb working with a compound known as abatacpet, marketed as Orencia. Abatacept is the first in a new class of drugs: costimulation modulators, that act on auto-immune disease by blocking the key co-stimulation signal (delivered by B7 interaction with CD28) needed to fully activate T cells. Orencia is approved for use in adult rheumatoid arthritis. I am currently Medical Monitor for studies using Orencia: 2 studies in systemic lupus erythematosus and one in juvenile idiopathic arthritis. I am also involved in developing future studies using Orencia in other auto-immune diseases.

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Roger Strair, MD, Ph.D. Research Activities Roger Strair’s laboratory focuses on translational research in hematologic malignancies. He designed and is the principal investigator on several investigator-initiated clinical trials. In addition, the Strair laboratory: (i) performs correlative studies to support the clinical trials; and (ii) undertakes novel laboratory studies utilizing primary malignant cells obtained from patients with hematologic malignancies. These laboratory studies are designed to direct the development of new therapies and identify new therapeutic targets. Included in these studies are: (1) development of new cellular immunotherapeutic strategies; and (2) analysis of primary mantle cell lymphoma cells. The clinical trials he has designed: (i) utilize new strategies (“Partially HLA-matched Allogeneic Hematopoietic Stem Cell Transplantation after Reduced Intensity Total Body Irradiation”); (ii) use novel immunotherapeutic approaches (“A Pilot Study of Irradiated HLA-Identical/Haploidentical Allogeneic Related Donor Lymphocytes as Consolidative Therapy Following Selected Anti-Neoplastic Therapies”); (iii) use therapy directed at new targets (“A Pilot Study of Nuclear Factor-kappa B (NFkB) Inhibition During Induction Chemotherapy for Patients with Acute Non-lymphocytic Leukemia (ANLL)”; (iv) evaluate the biological foundation of lymphoma formation ("Somatic Mutations During Lymphoma Formation") and (v) test new alternate therapies ("Clinical Effects of Green Tea in Patients with Indolent Chronic Lymphocytic Leukemia"). Teaching Dr. Strair actively participates in the teaching of undergraduates at Rutgers University, graduate students, medical students, interns, residents, hematology-oncology fellows and other physicians, nurses and patient support groups. This teaching occurs in the context of seminars, other didactic sessions, journal clubs, research seminars, lectures, and as a speaker at meetings. Generally, his teaching includes the following: Hematology Course for entire second year medical student class (3 hours) – 9/13/04 Internal Medicine Residents (during clinical clerkships): - lectures on hematologic malignancies, anemia, acute leukemia, the immune system,

development of lymphoma, Hodgkin’s lymphoma, multiple myeloma, hematopoietic stem cell transplantation

- case presentations - Morning Report Hematology-Oncology Fellowship Program: - Weekly lectures - Case Conferences – Pathology Conference, Lymphoma Conference,

Hematopoietic Stem Cell Transplantation Conference (weekly)

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July 12, 2004, Teaching Lecture, “Leukemia & Lymphoma, RWJUH Nursing Staff September 15, 2004, Teaching Lecture to Nurses – “Advances in Stem Cell Transplantation” Oncology Issues & Trends, Jersey City, NJ

November 4, 2004, Teaching Lecture -“Understanding Hematopoietic Stem Cell Transplantation", -“BMT Program”, RWJUH, New Brunswick, NJ

Teaching is also rendered while performing Attending duties at RWJUH: 7/01/04-7/31/04 - Hem/Onc & BMT Residents: 2 Fellows: Edward Lecitra, Yaqoob Ali 10/01/04-10/31/04 - BMT Residents: 0 Fellows: Anuradha Thalasila 10/30/04-10/31/04 Hem/Onc. (for Dr. Bertino) Residents: 2 Fellow: Edward Licitra 1/01/05-1/31/05 Hem/Onc & BMT Residents: 2 Fellows: Yaqoob Ali, Lisa Mills 11/20/04 – 11/22/04 Hem/Onc & BMT Residents: 2 Fellows: Lisa Mills, Kim Hirshfield 4/01/05 – 4/30/05 BMT Residents: 0 Fellows: Shayma Master Publications Schaar DG, Liu H, Sharma S, Ting Y, Martin J, Krier C, Ciardella M, Osman M, Goodell

L, Notterman DA, Strair RK. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced dual-specificity phosphatase expression and AML cell survival. Leukemia Research. 29(2005) 1171-1179. 2005.

Medina DJ, Sheay W, Osman M, Goodell L, Martin J, Rabson AB, Strair RK. Adenovirus Infection and Cytotoxicity of Primary Mantle Cell Lymphoma Cells. Experimental Hematology, 33, 1337-1347, 2005.

Schaar D, Goodell L, Aisner J, Cui XX, Han JT, Chang R, Martin J, Grospe S, Dudeck L,

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Riley J, Lin Y, Rubin EH, Conney A, Strair RK. A Phase I Clinical Trial of 12-O-tetradecanoylphorbol-13-acetate for Patients with Relapsed/Refractory Malignancies. Cancer Chemotherapy Pharmacology. 2005 Oct. 18;:1-7 (epub ahead of print).

Presentations Sept. 30, 2004, Invited Speaker, “Meet the Expert”, Leukemia & Lymphoma Society,

Clinical Academic Bldg., RWJUH October, 5, 2004, Invited Speaker, "What You Need To Know About Leukemia”,

Leukemia & Lymphoma Board of Trustees, Morristown, NJ January 12, 2005, Invited Speaker, "Novel Therapies for Mantle Cell Lymphoma” Mantle

Cell Workshop - Marriott Hotel, NY, NY February 17, 2005, Invited Speaker, “Focusing on Targeted Therapies in the

Treatment of non-Hodgkin’s Lymphoma” “Ask the Doctor” – Lymphoma Research Foundation, Rutgers Prep, New Brunswick, NJ

February 26, 2005, Invited Speaker, “Coping with Lymphoma” – Leukemia & Lymphoma Society, Short Hills Hilton, Short Hill, NJ

May 10, 2005, Invited Speaker, "Novel Immunotherapies" Faculty Meeeting – CINJ May 12, 2005, Invited Speaker, "Translational Studies in Hematologic Malignancies"

Pathology Grand Rounds - UMDNJ Newark, NJ May 18, 2005, Invited Speaker, “Bone Marrow Transplant Update”, Board of Directors,

Professional Affairs Committee, RWJUH, New Brunswick, NJ May 21, 2005, Invited Speaker, “Overview of Bone Marrow Transplantation

(Allogeneic)”, Professional Education Program, Lighthouse Int’l Conf. Center, NY, NY

Honors Promoted to Professor of Medicine, UMDNJ/Robert Wood Johnson Medical School, The Cancer Institute of New Jersey. 7/1/04. Administrative Committees

Departmental/University:

Director, Bone Marrow Transplant Unit, RWJUH The Cancer Institute of NJ

Allogeneic Bone Marrow Transplant Committee Blood and Marrow Transplant Performance Improvement Committee Lymphoma Study Group Task Force to Improve CINJ Medical Practice

External: Board of Trustees for Lymphoma & Leukemia Society

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Michael Steinmetz, Ph.D. Research Activities Michael Steinmetz, Ph.D. is Managing Director at Clarus Ventures, a venture capital firm with offices in Boston and San Francisco, focused on investments in biotechnology and medical device companies in the USA and Europe. The firm is currently investing its first $500MM fund. More information can be found on our website: www.clarusventures.com George B. Weiss, Ph.D. Dr. Weiss has retired and moved full-time to Tucson Arizona and was not active in research or university activities this past year. Lawrence P. Wennogle, Ph.D. Research Activities Intra-Cellular Therapies, Inc. (ITI) is a pharmaceutical company founded by Dr. Paul Greengard of Rockefeller University, Nobel Laureate in 2000 for his pioneering work on signal transduction in the central nervous system (CNS). ITI is developing novel therapeutics for disorders of the CNS including schizophrenia, depression and neurodegenerative disorders such as Parkinson’s and Alzheimer’s Diseases. I head a Drug Discovery effort including a Medicinal Chemistry, Pharmacology and Assay Development Departments. Currently, ITI is involved in pre-clinical development of a pipeline of compounds. We plan our first human clinical trials for schizophrenia in 2006. Publications Hekman M, Fischer A, Wennogle LP, Wang YK, Campbell SL, Rapp UR. Novel C-Raf

phosphorylation sites: serine 296 and 301 participate in Raf regulation. FEBS Lett. 2005 Jan 17;579(2):464-8.

Carol Wilusz, Ph.D.

Research Activities My research is closely linked with that of Dr Jeffrey Wilusz who is Department Head here at CSU. The lab has two main focuses, general mRNA metabolism and the interface between mRNA decay machinery and viral RNAs. With regard to mRNA metabolism we have identified a protein, Nucleophosmin, which is deposited specifically

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on mRNAs that have undergone polyadenylation. Current research is directed at finding the downstream effects on mRNA function of nucleophosmin binding. We have also shown that an RNA binding protein, CUG-BP, binds to the PARN deadenylase and influences its action. This is the first evidence of a direct effect of an RNA binding protein on a deadenylase. With regard to viral RNA stability, we have identified sequences within the 3’ UTR of two alphaviruses (VEE and SINV) that inhibit mRNA deadenylation in vitro. Current research is aimed at identifying the mechanism of inhibition and determining whether this observation can be recapitulated in cells. We have also found that the 5’ poly(A) tract found in poxvirus mRNAs is able to inhibit mRNA decay through interaction with Lsm proteins. Teaching (at CSU)

MB700 Topics : Post-transcriptional Control of Gene Expression This was a graduate seminar course. I co-ordinated the course, selecting relevant papers from the literature for students to present.

Publications

Duttagupta R, Tian B, Wilusz CJ, Khounh DT, Soteropoulos P, Ouyang M, Dougherty JP, Peltz SW. Global analysis of Pub1p targets reveals a coordinate control

of gene expression through modulation of binding and stability. Mol Cell Biol. 2005 Jul;25(13):5499-513.

Fritz DT, Bergman N, Kilpatrick WJ, Wilusz CJ, Wilusz J. Messenger RNA decay in Mammalian cells: the exonuclease perspective. Cell Biochem Biophys. 2004;41(2):265-78.

Wilusz CJ, Wilusz J. Bringing the role of mRNA decay in the control of gene expression into focus. Trends Genet. 2004 Oct;20(10):491-7. Review

Presentations May 24-29 RNA2005 Banff (presenter in bold) Palaniswamy, Wilusz C.J. & Wilusz J.

Nucleophosmin is deposited on mRNA during polyadenylation (talk) Bergman, Moraes, Wilusz C.J. & Wilusz J. The 5’ poly(A) tract of poxvirus inhibits

mRNA decay and binds to Lsm proteins (talk) Moraes, Wilusz C.J., & Wilusz J. CUG-BP and 3’UTR sequences influence PARN

mediated deadenylation in mammalian cells (poster) I was author on numerous other abstracts, but the RNA meeting was the only one I

attended.

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Service (at CSU) Alternate on CSU Radiation Committee Member of Search Committee to hire a Prion Biologist Assistant Professor

Junxia Xie, Ph.D. Research Activities My research interest is mainly focused on the interaction of cytokine receptors and the molecular changes that govern the cytokine mediated cell signaling. We used fluorescence resonance energy transfer (FRET), a non-invasive and powerful spectroscopic technique, to investigate the nature of receptor chain interaction in a complex. Using FRET assay, we have shown that IFN-γ receptor complex is an intimately pre-associated macromolecule complex. The binding of IFN- γ results in the separation of the intracellular domains of the receptor complex, thus enabling subsequent recruitment of Stat1 and the activation of the signaling pathway.

To investigate the real time movement of the intracellular domain of the IFN-γ receptor chains, we studied the kinetics of the receptor move during the IFN-γ ligand binding process. CHO q3 cells stably transfected with Hu-IFN-γR1-CFP and Hu-IFN-γR2-YFP cDNA were used for the receptor complex kinetic study. Our data show that upon IFN-γ binding, the immediate FRET signal reduction (measured as the yellow fluorescence intensity) and thus the separation in the intracellular domains of the IFN-γR1 and IFN-γR2 chains occur right after IFN-γ binding. It appears that there are two phases in the chain movement. The first movement is in small scale that happens immediately following the ligand binding and reach a steady state around 2-5 minutes; and the second movement in relative large scale starts at about 5 minutes after IFN-γ, which also reach steady state at about 12-15 minutes. We hypothesize that the first phase of FRET signal reduction between the intracellular domain of γR1 and γR2 chains is likely due to the separation between two γR1 homologous chains constrained by the ligand binding. The second phase of the chain separation between γR1 and γR2 chains may result from the phosphorylation on the intracellular domain of the γR1 chain through Jak1, Jak2 activation and subsequent recruitment of Stat1 molecule. Further experiments with kinetics of γR1 and γR2 movement showed that the second phase of kinetics is eliminated under conditions that blocks IFN-γ signaling such as in Stat1- cells or in the presence of Jak kinase inhibitor. These results are consistent with our hypothesis. With further kinetic study, we could also probe the molecular moiety along the down stream signal transduction pathway. For the later part of 2005, I started a new project at Zenotechinc, a biopharmaceutical company. My research focus is currently on the molecular mechanism of anticancer drug such as monoclonal antibodies, and is responsible for the design and generation of monoclonal antibody with higher affinity and avidity for cancer therapy.

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Teaching Microbiology and Immunology Course MGMB 6000

Publications

Xie, J., Krause, C.D., Schwartz, B., Mirochnitchenko, O., Jia, Y., and Pestka, S. (2004) Biphasic kinetics of conformational change in IFN-γ receptor complex in response to ligand binding. Abstract for Cytokines in Cancer and Immunity (Oct. 21-25. San Juan, Puerto Rico).

Gupta, S., Xie, J., Ma, J., and Davis, P.B. (2004) Intermolecular interaction between R domain of cystic fibrosis transmembrane conductance regulator. American Journal of Respiratory Cell Molecular Biology Feb; 30(2): 242-8

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CORE FACILITIES DNA Sequencing and Synthesis Core Facility The DNA Synthesis and Sequencing Core Facility of the Department of Molecular Genetics and Microbiology serves as a shared resource for the Cancer Institute of New Jersey (CINJ) and The National Institute of Environmental Health Sciences (NIEHS) Center at the Environmental and Occupational Health Sciences Institute (EOHSI) Center of Excellence. The overall purpose of this shared resource is to provide a centralized, high quality, cost-effective facility for DNA sequencing and synthesis for use by the entire scientific community at RWJMS and Rutgers University. Lee Ann Schein, Ph.D. serves as the Director of this facility. Automated fluorescent sequencing provides much more data (generally 400 to 850 nucleotides) from a single loading than can be achieved by manual sequencing methods most researchers previously performed in their laboratories. The cost of such a system is prohibitively high, thus only a shared resource such as the DNA laboratory can maintain and operate this system efficiently. The facility run two state of the art ABI 3100 capillary sequencers with a capacity of two 96 well plates per machine. For DNA Sequencing, CINJ and NIEHS members pay $9 per sequence with 400 bases of sequence guaranteed; this rate is 18% less than charged to other academic users ($11). User fees are designed to defray reagent costs and operating expenses, while ensuring members access to a state-of-the-art facility at low cost. The high throughput of the DNA sequencer and the use of two trained staff members for DNA sequencing now results in a typical turnaround time of 1 day for most sequencing. Thus, researchers are freed from performing these critical support experiments for their work, and can focus on the application of these technologies to addressing the important questions in their research programs. By providing synthetic oligonucleotides to all members of the University, many studies are greatly facilitated at significant cost discounts over what individual laboratories could obtain. The DNA Synthesis pricing policy reflects a significant discount on the list prices from IDT, the commercial provider of the service, based on the bulk orders placed by the facility. The DNA synthesis and sequencing facility serves our entire scientific community at RWJMS and Rutgers University. This is an example where our Departmental resources have been used to develop a core facility that is essential for the scientific development of RWJMS. Flow Cytometry and Cell Sorting Facility The Flow Cytometry and Cell Sorting Core Facility is a departmental core comprised of a FacScan Analyzer and a FacSvantage SE with Diva and is located in the Staged Research Building with Dr. Yufang Shi as the Director. Flowcytometers can measure several parameters on many thousands of individual cells in a short time, by detecting

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their fluorescence and the way they scatter light. This facility provides services to many labs of our department for cell sorting, cloning, and analysis for cell surface markers, intracellular proteins, and cell cycle. Outside investigators may use this facility by paying a membership fee and provide their own reagents. Fluorescence Resonance Energy Transfer Facility This year sees the beginning of a new core facility for the Department. The Real-Time Fluorescence Resonance Energy Transfer Facility, directed by Christopher D. Krause, PhD., was established. The purpose of this facility is to observe interactions between proteins in intact cells using Fluorescence Resonance Energy Transfer (FRET). Equipment leasing funds were used to purchase the necessary instruments and build the machine. A confocal microscope (Olympus IX71FVSF confocal microscope) was coupled to a spectrophotometer (Acton SP-150 Spectrophotometer) so that fluorescent emission spectra as well as spatial imaging can be obtained from light emitted from a confocal scanning of a biological sample. Samples are illuminated either by transmitted light and visualized by light microscopy or differential image contrast microscopy (Nomarsky microscopy), by widefield epifluorescence using a mercury lamp as the excitation source, or by laser excitation from either of five continuous wave lasers: a solid-state helium-cadmium laser emitting 442 nm light, an argon laser emitting both 488 and 514 nm light, a 532 nm helium-neon laser, or a 633 nm helium-neon laser. This instrument is one of the first in the nation to rigorously measure Fluorescence Resonance Energy Transfer in real time in cells with the use of cyan and yellow fluorescence proteins by capturing the full spectra of the fluorescence transfer to precisely ascertain the quality of the interactions between proteins in live cells. (See Krause et al., Molecular and Cellular Proteomics, 1, 805-815, 2002 for further details.) Phosphorimager Facility Dr. Jeffry Cook (PI) served as the Director of this facility along with Dr. Gary Brewer as Associate Director (Co-PI). Upon Dr. Cook’s departure from the Department, Dr. Brewer is the Director (PI) of this facility. The Imaging Facility consists of an Amersham Biosciences 9410 variable mode imager. The unit is housed in the Research Tower of the Piscataway, NJ campus. This instrument can detect and analyze fluorescent, chemiluminescent and radioactive signals. The phosphorimager requires the use of Molecular Dynamics cassettes for analysis of radioactive samples. The cassettes can be used with 3H, 14C, 35S, as well as 32P and 33P. All members of the department use the instrument without charge for facility use. Other investigators pay an annual user fee of $400 to help cover the cost of the service contract. The Director trains users and any of their staff at periodic training sessions. Appropriate supplies are provided by the department to cover the costs of its use. Investigators who wish to use the facility will be trained by the Director of the facility and/or his staff.

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Real-Time PCR Facility Real-time reverse transcription (RT) polymerase chain reaction (PCR) is the most sensitive and reliable method for the detection and quantitation of nucleic acids levels. A Stratagene Mx-4000 Multiplex Quantitative System provides an accurate method for real time determination of PCR products as they accumulate during PCR and thus enables accurate quantitation of the levels of specific DNA and RNA sequences in multiple tissue samples. This system is based on detection of fluorescent signals. The Real-Time PCR Core is located in the Staged Research Building. Dr. Yufang Shi is the Director of this facility and it is used by many labs in the department.

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DOCTORAL PROGRAM IN

MOLECULAR GENETICS, MICROBIOLOGY, and IMMUNOLOGY

Program Description The Graduate Program in Molecular Genetics, Microbiology, and Immunology offers a comprehensive program leading to the Ph.D. for graduate students anticipating careers as investigators and teachers. An M.D./Ph.D. program is also available. Graduate studies include formal training in biochemistry, molecular and cell biology, immunology, virology and elective courses based on the student’s own interest, selected from among the offerings at UMDNJ-Robert Wood Johnson Medical School (RWJMS) and Rutgers, The State University of New Jersey. Course work is supplemented by seminars, journal clubs and laboratory rotations designed to provide students with a broad background in the theory and methodology of molecular and cell biology. The program offers research opportunities in the Department of Molecular Genetics, Microbiology, and Immunology of UMDNJ-Robert Wood Johnson Medical School and other departments of RWJMS, as well as Rutgers University, the New Jersey Center for Advanced Biotechnology and Medicine, the Cancer Institute of New Jersey, and the Environmental and Occupational Health Sciences Institute. Research training is provided in many aspects of molecular genetics, microbiology, and immunology, including cellular immunology, molecular genetics of eukaryotic and prokaryotic cells, the interaction of viruses with host cells, retrovirology, nucleic acid and protein structure, structure and action of interferon receptors, transmembrane signal transduction and many other areas.

Program Consolidation and Coordination To improve recruitment of graduate students to this campus and to provide a comprehensive first year curriculum, the Graduate Program in Molecular Genetics, Microbiology, and Immunology merged its recruitment and admissions activities somel years ago with those of six other Coordinated Graduate Programs of Rutgers University and UMDNJ-Graduate School of Biomedical Sciences. This effort is designated the Consolidated Graduate Program in the Molecular Biosciences. These seven programs sponsor a shared first year Core Curriculum of graduate courses; these courses are taught by members of all participating programs.

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Molecular Genetics and Microbiology Graduate Program

GRADUATE STUDENT PROGRAM MENTOR ENTRY DATE

BANIHASHEMI, Lili GSBS Micro Gary Brewer, PhD 9/1/04

CABAN-VEGA, Hector GSBS Paul Coplend, PhD 9/1/02

CABAN, Kelvin GSBS Micro Paul Copeland, PhD 9/1/03

CHESONI, Sandra GSBS Micro Gary Brewer, PhD 9/1/03

DEFREN, Jennifer GSBS Micro Gary Brewer, PhD 9/1/03

DUTTAGUPTA, Radharani GSBS Micro S. Peltz, PhD 7/1/00

FRIKKER, Danielle GSBS Micro Honghua Li, PhD 9/1/01

GRATACOS, Frances Joint Micro Gary Brewer, PhD 9/1/03

GREEN, Yvette GSBS Micro Terri Goss Kinzy, PhD 9/1/02

GUPTA, Malivika GSBS Micro Gary Brewer, PhD 7/1/04

HU, Guohong GSBS Micro Honghua Li, PhD 2/1/03

LEE, Rose GSBS Micro Joseph Dougherty, PhD 9/0/04

*LIAO, Willey GSBS Micro S.Peltz, Ph.D. MGMI, 9/1/02

LIU, Mohan GSBS Micro Nancy Woychik, PhD 6/1/04

MICHEVA-VITEV, Sofiya GSBS Micro Joseph Dougherty, PhD 9/1/02

MUKHERJEE, Sayandip GSBS Micro Joseph Dougherty, PhD 9/1/01

ORTIZ, Pedro GSBS Micro Terri Goss Kinzy, PhD 9/1/00

OZTURK, Sedide GSBS Micro Terri Goss Kinzy, PhD 9/1/03

PHELAN, Bradley GSBS Micro Joseph Dougherty, PhD 9/1/03

PRYSAK, Meredith GSBS Micro Nancy Woychik, PhD 9/1/01

RUIDIAZ, Estelle GSBS Micro Gary Brewer, Ph.D. 9/1/02

SUTPHEN, Kristina GSBS Micro Gary Brewer, Ph.D. 9/1/02

SWAIMS, Alison GSBS Micro Arnold Rabson, M.D. 9/1/03

YANG, Zhihong GSBS Micro Sidney Pestka, MD 9/1/00

* Masters

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Students Receiving Ph.D Degrees Jin Hyung Lee, defended 1/14/2005 Jianling Zhuang, defended 3/16/05 Radharani Duttagupta, defended 4/14/05 Danielle Frikker, defended 4/27/05 Guohong Hu, defended 6/14/05

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PA Microbiology 2005 – Schedule

Lectures and examinations are held in the East Lecture Hall (ELH) Lab exercises are held in Rooms N-2 to N-6 & N-7 to N-11 on the second floor of the Teaching

Laboratories

Week 2: August 15-19

Tues 16 Aug 1:00 – 3:00 Lecture 1: Introduction to medical microbiology

Lecture 2: What kinds of microbes cause disease?

Wed 17 Aug 1:00 – 3:00 Lecture 3: Structure of bacterial cells

Workshop: Serial dilutions (ELH)

Thurs 18 Aug 1:00 – 3:00 Math & Chemistry Exam

Fri 19 Aug 1:00 – 3:00 Lecture 4: Bacterial genomes

Lecture 5: Bacterial Genetics-1

Week 3: August 22-26

Tues 23 Aug 1:00 – 4:00 Lecture 6: Bacterial Genetics-2

Lab 1: Normal flora Transmission of bacteria

Wed 24 Aug 1:00 – 4:00 Lecture 7: Sterilization & disinfection; precautions against infection

Review for Exam I Thurs 25 Aug 1:00 – 4:00 Lab 1: Results and Discussion

Fri 26 Aug 1:00 – 4:00 Exam I: Lectures 1-7 Lab 1

Week 4: August 30 – September 2

Tues 30 Aug 1:00 – 4:00 Lab 2: Microscopy and culture of bacteria

Wed 31 Aug 1:00 – 3:00 Lecture 8: Immunity

Lecture 9: Antibodies -1

Thurs 1 Sept 1:00 – 3:00 Lab 2: Results and discussion

Fri 2 Sept 1:00 – 3:00 Lecture 10: Antibodies -2

Lecture 11: Rxn between antigen & antibody - 1

Week 5: September 5-9

Tues 6 Sept 1:00 – 4:00 Lab 3: Nutritional requirements; Urine culture

Wed 7 Sept 1:00 – 3:00 Lecture 12: Rxn between antigen & antibody -2

Lecture 13: Complement Thurs 8 Sept 1:00 – 4:00 Lecture 14: Cells & tissues of the immune system -1

Lab 3: Results & discussion

Fri 9 Sept 1:00 – 3:00 Lecture 15: Cells & tissues of the immune system -2

Lecture 16: Cells & tissues of the immune system -3

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Week 6: September 12-16

Tues 13 Sept 1:00 – 4:00 Lab 4: Gram stain; Unknown 1

Thurs 15 Sept 1:00 – 3:00 Lecture 17: Cytokines

Lecture 18: Transfusion immunology

Fri 16 Sept 1:00 – 3:00 Lecture 19: The MHC

Lecture: 20 Transplantation Immunology

Week 7: September 19-23

Tues 20 Sept 1:00 – 4:00 Lab 5a: RID

Lab 5b: Blood typing

Wed 21 Sept 1:00 3:00 Lecture 21: Inflammation

Lecture 22: Hypersensitivity

Thurs 22 Sept 1:00 – 4:00 Lecture 23: Immuno-deficiency

Labs 5a/5b: Results and Discussion

Fri 23 Sept 1:00 – 4:00 Lecture 24: Antibiotics – 1

Lecture 25: Antibiotics – 2

Review for Exam II

Week 8: September 26-30

Tues 27 Sept 9:00 – 12:00 CGM: Course Introduction; Cell membranes

CGM: Overview of cell structure

CGM lab: Use of the microscope & cytology

1:00 – 3:00 Exam II: Lectures 8-23; Labs 2-5a/5b; Cumulative component

Wed 28 Sept 1:00 – 3:00 Lecture 26: Bacteria and disease

Lecture 27: Neisseria

Thurs 29 Sept 10:00 – 12:00 CGM: Receptors & cell signaling

CGM: Apoptosis

1:00 - 3:00 Lecture 28: Streptococci

Lecture 29: Staphylococci

Fri 30 Sept 9:00 – 12:00 CGM: Protein synthesis Cell secretion

CGM: Endosome/lysosome pathway

CGM lab: Cytology

1:00 – 4:00 Lecture 30: Gram-negative rods-1

Lecture 31: Gram-negative rods-2

Cases 1: Pyogenic cocci

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Week 9: October 3-7

Tues 4 Oct 9:00 – 12:00 CGM: Cell adhesion molecules

Cell junctions

CGM: Introduction to epithelia

CGM lab: Epithelia

1:00 – 4:00 Lab 6: Neisseria

Wed 5 Oct 1:00 – 3:00 Lecture 32: Gram-negative rods-3

Lecture 33: Gram-positive rods

Thurs 6 Oct 10:00 – 12:00 CGM lab: Epithelial tissue

1:00 – 4:00 Lecture 34: Gram-negative anaerobes

Lab 6: Results & discussion

Fri 7 Oct 9:00 – 12:00 CGM: Extracellular matrix (ECM) ECM receptors

CGM: Introduction to connective tissue

CGM lab: Connective tissue

1:00 – 4:00 Lecture 35: Chlamydia, Rickettsia, Ehrlichia

Lecture 36: Mycoplasma & Spirochetes

Cases 2: Gram-negative rods

Week 10: October 10-14 Tues 11 Oct 9:00 – 12:00 CGM: Review

Blood & myeloid tissue

Lab: Connective tissue 1:00 – 5:00 Lab 7: Gram-positive Unknown

Wed 12 Oct 1:00 – 4:00 Lab 7: Gram-positive Unknown

Thurs 13 Oct 10:00 – 12:00 CGM: Structure & function of cartilage

CGM: Introduction to cartilage & bone

Lab: Blood & cartilage

1:00 – 4:00 Lecture 37: Fungi

Lab 7: Gram-positive Unknown

Fri 14 Oct 9:00 – 12:00 CGM: Bone: structure, function, & development

Lab: Cartilage & Bone

1:00 – 3:00 Lecture 38: Mycobacteria

Cases 3: Gram-positive rods, anaerobes, etc.

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Week 11: October 17-21 Tues 18 Oct 9:00 – 12:00 CGM: Cytoskeletion

Introduction to skeletal muscle

Lab: Muscle tissue 1:00 – 4:00 Lab 8: Gram-negative unknown

Wed 19 Oct 1:00 – 5:00 Lecture 39: Mycoses

Lab 8: Gram-negative unknown

Thurs 20 Oct 10:00 – 12:00 CGM: Molecular motors

Muscle contraction

1:00 – 5:00 Lecture 40: Protozoa – 1

Lab 8: Gram-negative unknown

Fri 21 Oct 9:00 – 12:00 CGM: Cardiac & smooth muscle

Lab: Skeletal Cardiac & Smooth muscle

1:00 – 3:00 Lecture 41: Protozoa – 2

Cases 4: Mycobacteria, etc.

Week 12: October 24-28 Tues 25 Oct 9:00 – 12:00 CGM: Neurocytology (2 lectures)

Introduction to neural tissue

Lab: Neural tissue

1:00 – 4:00 Lecture 42: Introduction to Virology – 1

Lab 8: Gram-negative unknown

Lab 9: Haemophilus, Clostridium, Mycobacterium

Wed 26 Oct 1:00 – 3:00 Lab 8: Gram-negative unknown

Lab 9: Haemophilus, Clostridium, Mycobacterium

Thurs 27 Oct 10:00 – 12:00 CGM: Stem cells

Neuro-regeneration

Lab: Neural tissue

1:00 – 4:15 Lab 10: Fungi

Review for Unknown IV (in lab)

Fri 28 Oct 9:00 – 12:00 CGM: Exam Review

Practice Practical Exam

1:00 – 4:00 Lecture 43: Introduction to Virology – 2

Cases 5: Fungi & Protozoa

Review for Exam III

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Week 13: October 31-November 4 Tues 1 Nov 1:00 – 3:00 Exam III

Lectures 24-41 Cases 1-5 Labs 6-10 Cumulative component

Wed 2 Nov

Thurs 3 Nov

Fri 4 Nov 9:00 – 12:00 CGM: Exam I

Week 14: November 7-11 Mon 7 Nov 10:00 – 12:00 CGM: DNA -

Structure Replication Repair Recombination (2 lectures)

1:00 – 4:00 Lab 11: Unknown 4

Tues 8 Nov 1:00 – 4:00 Lab 11: Unknown 4

Wed 9 Nov 10:00 – 12:00 CGM: DNA -

Structure Replication Repair Recombination (2 lectures)

1:00 – 4:00 Lab 11: Unknown 4

Thurs 10 Nov 10:00 – 12:00 CGM: RNA synthesis (2 lectures)

1:00 – 4:00 Lecture 44: (-) Strand ssRNA viruses -1

Review for Lab Practical Exam (in lecture hall)

Lab 11: Unknown 4

Fri 11 Nov 1:00 – 3:00 CGM: RNA processing

CGM: Review 3:00 – 4:00 Lab 11: Unknown 4

Week 15: November 14-18 Mon 14 Nov 10:00 – 12:00 CGM: Protein synthesis (2 lectures)

Tues 15 Nov 1:00 – 5:00 Lab Practical Exam

Wed 16 Nov 10:00 – 12:00 CGM: Recombinant DNA (2 lectures)

1:00 – 3:00 Lecture 45: (-)strand ssRNA viruses -2

Lecture 46: (+)strand ssRNA viruses - 1

Thurs 17 Nov 10:00 – 12:00 CGM: Recombinant DNA

Skills session” Restriction Mapping and DNA sequencing

146

1:00 – 4:00 Lecture 47: (+)strand ssRNA viruses – 2 dsRNA viruses

Lecture 48: Retroviruses

Lecture 49: HIV

Fri 18 Nov 1:00 – 3:00 CGM: Mitosis & Chromosomes

CGM Review

3:00 – 4:00 Lecture 50: AIDS

Week 16: November 21-25 Mon 21 Nov 10:00 – 12:00 CGM: Control of the cell division cycle – 1

CGM: Control of the cell division cycle - 2

Tues 22 Nov 1:00 – 3:00 Lecture 51: Introduction to DNA viruses; Herpesviruses-1

Lecture 52: Herpesviruses-2

Wed 23 Nov 10:00 – 12:00 CGM: Human karyotype and genome

CGM: Cancer: cell biology & genetics

Thurs 24 Nov 1:00 – 4:00 Optional laboratory exercise: Anatomical dissection of Meleagris gallopavo

Week 17: November 28-December 2 Mon 28 Nov 10:00 – 12:00 CGM: Meiosis and recombination

CGM: Sex chromosome anomalies Autosomal trisomies

Tues 29 Nov 1:00 – 3:00 Lecture 53: Papovaviruses Adenoviruses

Lecture 54: HBV Poxvirus Parvoviruses

Wed 30 Nov 9:00 – 12:00 CGM: FISH

CGM: Clinical cytogenetics Imprinting

CGM: Pedigree Analysis

Thurs 1 Dec 10:00 – 12:00 CGM: Prenatal diagnosis

CGM: Population Genetics

1:00 – 3:00 Lecture 55: Prions

Review: Exam IV

Fri 2 Dec 1:00 – 3:00 CGM: Skill session: Cytogenetics FISH

CGM: Review

Week 18: December 5-9 Mon 5 Dec 10:00 – 12:00 CGM: Genetic counseling

CGM: Triplet expansion diseases

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Tues 6 Dec 1:00 – 3:00 Exam IV: Lectures 42-55

Cumulative component

Wed 7 Dec 9:00 – 12:00 CGM: DNA-based diagnostic tests

CGM: Microchip analysis of nucleic acids

CGM: Skills session:

Risk assessment

DNA tests

Thurs 8 Dec 10:00 – 12:00 CGM: Small-group -- Case Presentations

Fri 9 Dec 1:00 – 3:00 CGM: Mutations & phenotypes

CGM: Sexual differentiation disorders

Week 19: December 12-16

Mon 12 Dec 10:00 – 12:00 CGM: Genetic mapping

Skill session: single gene mapping

Tues 13 Dec 1:00 – 3:00 Microbiology: Review Session for Final Exam

Wed 14 Dec 9:00 – 12:00 CGM: Complex disorders – 1

CGM: Complex disorders – 2

CGM: Skills session: Complex disorders – 1

Thurs 15 Dec 10:00 – 12:00 CGM: Skills session: Complex disorders – 2

CGM: Exam review

Fri 16 Dec 1:00 – 3:00 Microbiology Final Exam Cumulative

Week 20: December 20-24 Wed 21 Dec 9:00 – 12:00 CGM: Exam II

148

CELLULAR AND GENETIC MECHANISMS 2004

WEEK DAY MONTH DATE TIME TOPIC LECTURER

8

Tues.

Sept.

28

9:00

Course introduction

W. Zehring, Ph.D.; F. Wilson, Ph.D.; M. Newlon, Ph.D.

9:50 Review of cell structure Frank Wilson, Ph.D.

10:35 Lab: Use of the microscope and cytology

Thurs. Sept. 30 10:00 Cell membranes Frank Wilson, Ph.D.

10:50 Cell receptors / cell signaling Frank Wilson, Ph.D.

Fri. Oct. 1 9:00 Cytoskeleton James Zheng, Ph.D.

10:00 Molecular motors Sarah Hitchcock- DeGregori, Ph.D.

10:45 Lab: Cytology

9 Tues. Oct. 5 9:00 Protein synthesis / cell secretion John Pintar, Ph.D.

10:00 Endosome/lysosome pathway John Pintar, Ph.D.

10:30 Introduction to epithelial tissue Frank Wilson, Ph.D.

10:45 Lab: Epithelial tissue

Thurs. Oct. 7 10:00 Cell adhesion molecules / cell junctions

Frank Wilson, Ph.D.

11:00 Lab: Epithelial tissue

Fri. Oct. 8 9:00 Extra-cellular matrix and ECM receptors

John Pintar, Ph.D.

10:30 Introduction to connective tissue Frank Wilson, Ph.D.

11:00 Lab: Connective tissue

10 Tues. Oct. 12 9:00 Stem cells and apoptosis Geoffrey McAuliffe, Ph.D.

10:00 Blood and myeloid cells Frank Wilson, Ph.D.

10:45 Lab: Connective tissue

Thurs. Oct. 14 10:00 Review

10:30 Introduction to cartilage and bone

Frank Wilson, Ph.D.

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CELLULAR AND GENETIC MECHANISMS 2004

WEEK DAY MONTH DATE TIME TOPIC LECTURER

11:00 Lab: Cartilage and bone

Fri. Oct. 15 9:00 Bone: structure, function, development

Sarah Hitchcock-DeGregori, Ph.D.

10:30 Lab: Cartilage and Bone

11 Tues. Oct. 19 9:00 Neurocytology – 1 Cheryl Dreyfus, Ph.D.

9:50 Neurocytology – 2 Cheryl Dreyfus, Ph.D.

10:30 Introduction to neural tissue Frank Wilson, Ph.D.

11:00 Lab: Neural tissue

Thurs. Oct. 21 10:00 Neuroregeneration Cheryl Dreyfus, Ph.D.

11:00 Lab: Neural tissue

Fri. Oct. 22 9:00 Muscle contraction Sarah Hitchcock-DeGregori, Ph.D.

10:50 Introduction to muscle tissue Frank Wilson, Ph.D.

11:15 Lab: Skeletal muscle

12 Tues. Oct. 26 9:00 Cardiac and smooth muscle Frank Wilson, Ph.D.

10:00 Lab: Cardiac and smooth muscle

Thurs. Oct. 28 10:00 Integrated presentation Duchenne muscular dystrophy

W. Zehring, Ph.D.; Frank Wilson, Ph.D.; M. Newlon, Ph.D.; D. Seiden, Ph.D.

Fri. Oct. 29 9:00 Review for Examination I

10:00 Practice Practical Examination

13 Fri. Nov. 5 9:00 Examination I (3 hrs)

14 Mon. Nov. 8 10:00 DNA structure, replication, repair, recombination

Celine Gelinas, Ph.D.

11:00 DNA structure, replication, repair, recombination

Celine Gelinas, Ph.D.

Wed. Nov. 10 10:00 DNA structure, replication,

repair, recombination Celine Gelinas, Ph.D.

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CELLULAR AND GENETIC MECHANISMS 2004

WEEK DAY MONTH DATE TIME TOPIC LECTURER

11:00 DNA structure, replication, repair, recombination

Celine Gelinas, Ph.D.

Thurs. Nov. 11 10:00 RNA synthesis Michael Hampsey, Ph.D.

11:00 RNA synthesis Michael Hampsey, Ph.D.

Fri. Nov. 12 1:00 RNA processing Michael Hampsey, Ph.D.

2:00 Review session

15 Mon. Nov. 15 10:00 Protein synthesis Marilyn Kozak, Ph.D.

11:00 Protein synthesis Marilyn Kozak, Ph.D.

Wed. Nov. 17 9:00 Recombinant DNA technology DNA sequencing

Yuh-Hwa Wang, Ph.D.

10:00 Recombinant DNA technology DNA sequencing

Yuh-Hwa Wang, Ph.D.

11:00 Review Session

Thurs. Nov. 18 10:00 Recombinant DNA technology DNA sequencing

Yuh-Hwa Wang, Ph.D.

11:00 Recombinant DNA technology DNA sequencing

Yuh-Hwa Wang, Ph.D.

Fri. Nov. 19 1:00 Gene therapy Kiran Chada, Ph.D.

2:00 Microchips and advanced recombinant DNA

Kiran Chada, Ph.D.

16 Mon. Nov. 22 10:00 Mitosis Cell cycle and its control

James Millonig, Ph.D.

11:00 Chromosomes, meiosis, non-disjunction

Michael Newlon, Ph.D.

Wed. Nov. 24 9:00 Human genome, gene mapping Michael Newlon, Ph.D.

10:00 Review session Michael Newlon, Ph.D.

17 Mon. Nov. 29 10:00 Pedigrees and patterns of inheritance

Michael Newlon, Ph.D.

151

CELLULAR AND GENETIC MECHANISMS 2004

WEEK DAY MONTH DATE TIME TOPIC LECTURER

11:00 Clinical cytogenetics and imprinting

Lenny Sciorra, Ph.D.

Wed. Dec. 1 9:00 Autosomal trisomies, Sex chromosome aneuploidies

Lami Yeo, M.D.

10:00 Dysmorphology Rhonda Schnur, M.D.

11:00 Acute metabolic syndromes

Newborn screening Rhonda Schnur, M.D.

Thurs. Dec. 2 10:00 Review session Michael Newlon, Ph.D.

11:00 Prenatal diagnosis Lami Yeo, M.D.

Fri. Dec. 3 1:00 Genetic counseling Elena Ashkinadze, M.S.

2:00 Review session Michael Newlon, Ph.D.

18 Mon. Dec. 6 10:00 Triplet expansions Yuh-Hwa Wang, Ph.D.

11:00 DNA diagnostic tests Michael Newlon, Ph.D.

Wed. Dec. 8 9:00 Alleles in populations Linda Brzustowicz, M.D.

10:00 Small group

11:00 Small group

Thurs. Dec. 9 10:00 Capstone presentation Colon Cancer

W. Zehring, Ph.D.; F. Wilson, Ph.D.; M. Newlon, Ph.D.; D. Seiden, Ph.D.

11:00 Sexual differentiation disorders Cynthia Meyers-Seifer, M.D.

Fri. Dec. 10 1:00 Complex phenotypes: Heredity and environment

L. Brzustowicz, M.D.

2:00 Complex phenotypes: Genes L. Brzustowicz, M.D.

19 Mon. Dec. 13 10:00 Cancer genetics and cytogenetics

Michael Newlon, Ph.D.

11:00 Review session Michael Newlon, Ph.D.

152

CELLULAR AND GENETIC MECHANISMS 2004

WEEK DAY MONTH DATE TIME TOPIC LECTURER

Wed. Dec. 15 9:00 Familial cancer syndromes D. Gibbon, M.D.

10:00 Small group

11:00 Small group

19 Thurs. Dec. 16 1:00 Review session Michael Newlon, Ph.D.

2:00 Review session Michael Newlon, Ph.D.

20 Wed. Dec. 22 9:00 Examination II (3 hrs.) Date of revision: 12 Aug 2004 By: M. Newlon

153

Medical Microbiology and Immunology–2005 T Lectures, Discussions, Case Presentations, and Exams are held in the Main Lecture Hall [MLH] unless otherwise specified. Laboratory Exercises meet in the Multi-discipline Labs S-212 and S-220, South Wing, second floor of the Teaching Laboratories. Patient-Oriented Problem-Solving [POPS] Exercises meet in Small Group Rooms C-1 – C-12, C-207, C-208.

Unit I: Immunology & Basic Bacteriology

Week 21: Cells and Tissues of the Immune System

Weds 5 Jan 10:30-11:20 11:30-12:20

Overview of the Course [Drs. Pestka, Newlon] [ELH, overflow in WLH] Lecture: Immunity and Inflammation [Dr. Newlon] [ELH/WLH]

Thurs 6 Jan 10:30-11:20 Lecture: Cells & Organs of the Immune System [Dr. Newlon] [ELH/WLH] Assigned reading: Cytokines, CD Antigens

Fri 7 Jan 9:30-10:20 Discussion: Identification of Immune-system Cells [ELH/WLH]

Week 22: Antibodies

Weds 12 Jan 10:30-11:20 Lecture: Antibodies [Dr. Li] Assigned reading: Immunization, Tumor Immunology

Thurs 13 Jan 10:30-12:20 POPS Exercise I – Immunity to Tetanus

Fri 14 Jan 9:30-10:20 Discussion: Antibody Structure Case presentation: Multiple Myeloma [MLH]

Week 23: Immunochemistry 10:30-11:20

Lecture: Immunochemistry [Dr. Kimball] Assigned reading: Serology: Diagnostic Use of Antibody-Antigen Reactions Assigned reading: Transfusion Immunology, Complement

Thurs 20 Jan 10:30-12:20 POPS – Jaundiced Baby

Fri 21 Jan 9:30-10:20 Discussion: Interpretation of Immunodiagnostic Tests; Blood Typing

154

Week 24: The Major Histocompatibility Complex [MHC] and its Roles in the Immune System

Weds 26 Jan 10:30-11:20

Lecture: The Major Histocompatibility Complex [Dr. Ron] Assigned reading in syllabus: Transplantation Immunology

Thurs 27 Jan 10:30-12:20 POPS – MI Sick

Week 25: Immunological Disease; Immunization

Weds 2 Feb 10:30-11:20

Lecture: Inflammation and Hypersensitivity [Dr. Shi] Assigned reading in syllabus: Immunodeficiency, Neuroimmunology

Thurs 3 Feb 10:30-12:20 POPS – Immediate Hypersensitivity

Fri 4 Feb 9:30-10:20 Discussion [MLH]: Diagnosis of Immunodeficiency Discussion [MLH]: Structure of Major Histocompatibility Antigens Discussion [MLH]: Pre-Transplantation Testing

1:00 Prep meeting for Lab 1

Week 26: Basic Bacteriology

Tues 8 Feb 8:30- 9:20 Lecture: Structure of Bacteria [Dr. Newlon]

Weds 9 Feb 10:30-11:20 11:30-12:20

Lecture: Genetics of Bacteria [Dr. Brewer] Lab 1 – Microscopy and Culture of Bacteria

Thurs 10 Feb 10:30-12:20 Lab 1 – Concluded

Fri 11 Feb 11:30-12:20 Q & A for Exam Review [MLH] [Optional]

Week 27: Exam I [Covers Weeks 21 – 26]

Fri 18 Feb 10:30-12:30 Exam I [in MLH]

155

Unit II: Medical Bacteriology; Fungi & Parasitic Protozoa

Week 28: Antimicrobial Agents

Weds 23 Feb 10:30-11:20 Lecture: Antibiotics [Dr. Copeland] Assigned reading in Syllabus: Phagocytes Assigned reading in Syllabus: Introduction to Medical Microbiology [NB: read through this lightly now and seriously when reviewing for the exam.]

Thurs 24 Feb 10:30-12:20 POPS – Antibiotics

Fri 25 Feb 9:30-10:20 Discussion: Antibiotic Sensitivity Testing; determination of MIC & MBC

1:00 Prep meeting for Lab 2

Week 29: Pyogenic Cocci

Weds 2 Mar 10:30-11:20 11:30-12:20

Lecture: Pyogenic Cocci [Lecturer TBA] Assigned reading in syllabus: Neisseria; Staphylococci; Streptococci ASM cases (on computers): 17, 26 (Skin and Soft Tissue infections,

3 (Respiratory tract infections), 2 (GU infections), 22 (CNS infections) Lab 2: Gram-positive cocci unknown (Report due 3/9)

Thurs 3 Mar 10:30-12:20 Lab 2 – Continued

Fri 4 Mar 8:30- 9:20 9:30-10:20

Discussion: Pyogenic Cocci; ASM CHx 2, 3, 17, 22, 26 Lab 2 – Concluded

1:00 Prep meeting for Lab 3

Week 30: Enterobacteriaceae and Related Bacteria

Weds 9 Mar 10:30-11:20 11:30-12:20

Lecture: Enterobacteriaceae & Relatives: [Dr. Newlon] ASM cases (on computers): 1 (GU infections), 5 (Respiratory tract infections), 12 (GI Infections) Lab 3 – Gram-negative rods unknown (Report due 3/16)

Thurs 10 Mar 10:30-12:20 Lab 3 – Continued

Fri 11 Mar 8:30- 9:20 9:30-10:20 1:00

Discussion: Enterobacteriaceae etc.; ASM CHx 1,5,12 Lab 3 – Concluded Prep meeting for Lab 4

Week 31: Gram-Positive Rods

Weds 16 Mar 10:30-11:20 11:30-12:20

Lecture: Anthrax [Dr. Godyn] Assigned Reading in Syllabus: Gram-Negative Rods – 2;

Gram-Negative Anaerobes; Gram-positive rods ASM Cases (on computers): 11 (Respiratory Infections, 16 (GI Infections) Lab 4 – CSF Unknown (Report due 3/23)

156

Thurs 17 Mar 10:30-12:20 Lab 4 – Concluded

Fri 18 Mar 9:30-10:20 Discussion: Gram-Positive Rods; Gram-Negative Rods; Anaerobes; ASM CHx 11, 16

Week 32: Mycoplasma, Spirochetes, Chlamydia, Rickettsia, Mycobacteria.

Weds 23 Mar 10:30-12:20 Infectious Disease Case Presentations: Bruce Fisher, M.D. [MLH]

Thurs 24 Mar 10:30-11:20 11:30-12:20

Lecture: Mycoplasma, Spirochetes, Chlamydia, Rickettsia. [Dr. Woychik] ASM Cases (on computers): 20 (Skin & Soft Tissue Infections), 33

(Emerging Infections) Assigned reading in syllabus: Mycobacteria ASM Cases (on computers): 4 (Respiratory Infections), 25 (CNS

Infections), 28 (Systemic Infections) Discussion: Q & A for Exam Review; Mycoplasma, etc.

Week 33: Parasitic Protozoa & Fungi

Weds 30 Mar 10:30-11:20 11:30-12:20

Lecture: Protozoa –1 [Dr. Leibowitz] Lecture: Protozoa – 2 [Dr. Leibowitz] ASM Cases (on computers): 14 (GI Infections), 21 (Skin & Soft Tissue

Infections), 30 (systemic Infections)

Thurs 31 Mar 10:30-11:20

11:30-12:20

Lecture: Fungi and Mycoses [Dr. Newlon] ASM Cases (on computers): 7-10 (Respiratory Tract), 23,24 (CNS

Infections), 27, 29 (Systemic Infections) Discussion: Protozoa; Fungi; ASM CHx 14, 21, 30; 7-10, 23-24; 27; 29

Week 34: Exam II

Mon 4 Apr 10:30-12:30 Exam II [in MLH]

Unit III: Viruses

Week 35: Biology of Viruses

Weds 13 Apr 10:30-11:20 11:30-12:20

Lecture: Introduction to Virology – 1 [Dr. Stollar] Lecture: Introduction to Virology – 2 [Dr. Stollar]

Thurs 14 Apr 10:30-12:20 Infectious Disease Case Presentations [Bruce Fisher, M.D.][MLH] Fri 15 Apr 9:30-10:20 Discussion: Introduction to virology, diagnosis of viral infections

157

Week 36: Viruses with Single-stranded RNA Genomes of (+) Polarity.

Weds 20 Apr 10:30-11:20

Lecture: HCV & Related Viruses [Dr. Stollar] Assigned Reading: Polio, other (+)ssRNA viruses; ds RNA viruses ASM Cases: 32, 44, 66 [in Book, not on computer]

Thurs 21 Apr 10:30-11:20 Infectious Disease Case Presentations [Bruce Fisher, M.D.][MLH]

Fri 22 Apr 9:30-10:20 Discussion: (+) Strand ssRNA Viruses ASM Cases: 32, 44, 66 [in Book, not on computer]

Week 37: Influenza and Related Viruses; DNA Viruses

Weds 27 Apr 10:30-11:20 11:30-12:20

Lecture: Influenza & Other Viruses with (-) ssRNA Genomes [Dr. Schein] ASM Cases (on Computers): 2 (GI Infections), 6 (Respiratory Infections),

19 (Systemic Infections) Lecture: Herpesviruses [Drs. Schein, Newlon] Assigned Reading: Pox/Parvo/Papova/Adenoviruses.

Thurs 28 Apr 10:20-12:30 POPS: Serological Diagnosis of Influenza

Fri 29 Apr 9:30-10:20 Discussion: (-)ssRNA & DNA Viruses [MLH]; ASM CHx 2, 6, 19

Week 38: Retroviruses, HIV, AIDS

Weds

4 May

10:30-11:20

Lecture: Retroviruses [Dr. Dougherty] ASM Case (on Computers): 31 (Emerging Infections) Assigned reading in syllabus: Hepatitis B virus; ds RNA Viruses

Thurs 5 May

10:30-11:20 11:30-12:20

Lecture: HIV [Dr. Rabson] Lecture: AIDS [Dr. Rabson]

Fri 6 May 9:30-10:20 ASM Cases (on computers): 18 (Skin and Soft Tissue Infectons), 32 (Emerging Infections)

Discussion: Retroviruses, HIV, AIDS; ASM CHx 31

Week 39: Antiviral Drugs; Interferons; Prions

Weds

11 May

10:30-11:20 11:30-12:20

Discussion: Antiviral Drugs, Interferons, Prions ASM Case 34; Q & A for Exam Review Lecture: Interferons [Dr. Pestka] Assigned Reading in Syllabus: Prions; Antiviral Drugs; ASM Case 34 [EM]

Week 40: Exam III

Fri 20 May 10:30-12:30 Exam III [in MLH]

158

HOLOWCZAK MEMORIAL FUND

The Holowczak Memorial Fund was established in 1986 in memory of Professor John A. Holowczak. Dr. Holowczak was a member of the Department of Molecular Genetics, Microbiology and Immunology for 18 years before his untimely death in 1986. The fund was established for travel awards for graduate students and postdoctoral fellows in this department. The interest earned to date is $20,826.07. The current balance is $27,128.30. This year travel awards were made to the following students: $500 to Kelvin Caban, $500 to Pedro Ortiz, and $500 to Meredith Prysak. This fund has been extraordinarily useful for the department as it supports the travel of MGMI students and fellows to attend scientific meetings and to make presentations at national and international symposia. It provides these developing investigators with exposure to other colleagues in their area of research, which is a very important part of their experience and maturation as productive scientists. This fund serves to honor Dr. Holowczak who was an extraordinary professor who was cherished by students, fellows and other members of the faculty and school.

159

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

GARY BREWER, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Post transcriptional Regulation 09/01/99- 1,415,483 236,750 25% of Health of Oncogene Messenger RNA" 11/30/06

US Army "RNA-Binding Proteins as Novel 01/01/03- 300,000 100,000 20% Oncoproteins and Tumor Suppressors" 12/31/05

National Institutes "Regulated c-myc Destabilization 07/01/02- 1,112,500 259,936 20% of Health during Differentation" 06/30/07

National Institutes "Adherence Activated Monocyte 07/15/04- 971,382 182,965 20% of Health Genes" 06/30/09

National Institutes "Role of mRNA Deacy in the Immune 07/15/04- 69,610 13,000 20% of Health System" Imaging Core Facility 06/30/09

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Direct Costs 792,651Current Indirect Costs 324816

TOTAL 1,117,467

160

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

PAUL R. COPELAND, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "The translational control of 08/01/03- 985,855 211,586 25% of Health selenoprotein synthesis" 07/31/08

Dean and Betty Gallo "The role of dietary selenium 11/01/04- 43,000 13,000 10% Prostrate Cancer Center in prostrate chemoprevention" 04/30/06

NJCCR "The role of selenocysteine 06/01/05- 3,200 3,200 0% in chemoprevention" 08/31/05 Awardee: Ruchira Ranaweera

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Direct Costs 227,786Current Indirect Costs 101,546

TOTAL 329,332

161

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

JOSEPH P. DOUGHERTY, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

National Institutes "Analysis of the Nonsense- 01/01/93- 1,662,207 270,816 25% of Health Mediated mRNA Decay Pathway" 12/31/05

National Institutes "A Complex Involved in mRNA 05/01/99- 1,499,973 200,000 30% of Health Decay in Yeast" 04/30/04

National Institutes "Translational Regulation by 07/15/04- 948,155 198,880 10% of Health the TNF Alpha AU-rich Element" 06/30/09

National Institutes "HIV Frameshifting-From 02/01/99- 810,008 0 10% of Health Biology to Therapeutics" 01/31/05PI: Dr. S. Peltz

Current Direct Costs 669,696Current Indirect Costs 347,339

TOTAL 1,017,035

162

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

TERRI GOSS KINZY, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Regulators of Translation 08/01/98- 679,543 239,779 30% of Health Elongation Factor 1 Alpha" 07/31/07

National Institutes "Structural Studies of 06/01/01- 688,715 0 10% of Health Translation Elongation Factor 1" 05/31/05

National Science "CAREER: Molecular Interactions and 09/01/00- 276,830 29,100 10% Foundation Nucleotide Exchange Mechanism of 08/31/06

Translation Factor EF1B Alpha"

National Institutes "Cancer Center Support Grant" 03/1/97- 467,939 105,549 15% of Health, NCI 02/28/05

Human Frontier Science "Structural and Functional 06/01/02- 262,500 0 5% Program Studies of the Yeast Ribosome" 05/31/06

Core Facility "DNA Synthesis/Sequencing 07/01/03- 498,652 498,652 Laboratory" 06/30/04

National Institutes "Analysis of translation 09/15/04- 57,930 28,965 of Health elongation factor 2 in yeast" 09/16/06

Awardee: Pedro Ortiz Sponsor: Terri Goss Kinzy

163

TERRI GOSS KINZY, PH.D. Continued

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 2% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

National Institutes "Role of mRNA Decay in 7/15/2004 132,728 25,000 2% of Health the Immune System" 06/30/09

DNA Core Facilty

NIEHS "Molecular Genetics Core 04/01/03- 148,300 33,088 10% Facility" 03/31/05

Current Direct Costs 960,133Current Indirect Costs 140,287

TOTAL 1,100,420

164

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

JEROME A. LANGER, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

Alliance for Lupus "Type I Interferon Antagonists 03/01/05- 418,210 216,560 25% Research for Lupus and Autoimmunity" 02/28/07

National Institutes "UMDNJ-Rutgers University 09/01/96- 1,645,247 0 25% of Health Pipeline-Initiative for Minority 02/28/09 PI: Dr. M. Leibowitz Student Development"

National Institutes "Bridge to the Doctoral Degree. 09/30/01- 354,814 0 10% of Health UPR to UMDNJ" 09/29/07 PI: Dr. M. Leibowitz

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Direct Costs 216,560Current Indirect Costs 17,325

TOTAL 233,885

165

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

MICHAEL J. LEIBOWITZ, M.D., PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "UMDNJ-Rutgers University 09/01/96- 4,882,628 433,515 10% of Health Pipeline-Initiative for Minority 02/28/09

Student Development"

National Institutes "Bridge to the Doctoral Degree. 09/30/01- 710,220 174,785 10% of Health UPR to UMDNJ" 09/29/07

National Science "A Novel Epigenetic Regulator 09/01/02- 250,592 76,041 20% Foundation of Viral Gene Expression in Yeast" 08/31/06

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

National Institutes "Biotechnology Training Grant" 07/01/88- 2,756,851 0 1% of Health 06/30/10 PI: Dr. H. Pederson

National Instutes MSU-UMDNJ-GSBS 07/01/05- 675,000 70,646 5% of Health Bridges to the Doctorate 6/30/2006

166

MICHAEL J. LEIBOWITZ, M.D., PH.D. Continued

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Enhancing Intestinal & Brain 04/01/02- 875,000 0 10% of Health Uptake of Anti-AIDS Drugs" 03/31/06 Participating Faculty PI: Dr. P. Sinko

Current Direct Costs 754,987Current Indirect Costs 71,444

TOTAL 826,431

167

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

HONGHUA LI, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Direct Costs 0Current Indirect Costs 0

TOTAL 0

168

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

SIDNEY PESTKA, M.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 149,306 10% of Health Eukaryotic Cells" 08/31/08

National Institutes "Cancer Center Support Grant" 03/01/97- 53,256 10,503 7% of Health 02/28/04

National Institutes "Receptor-Signaling Protein 04/01/04- 900,000 225,000 5% of Health Interactions in Real Time" 03/31/08

National Institutes "Regulation of Cytokine Gene 07/15/04- 955,646 180,000 10% of Health Expression by mRNA Turnover" 06/30/09

National Institutes "Role of mRNA Decay in the 07/15/04- 250,591 47,200 2% of Health Immune System" 06/30/09

Administrative Core

National Institutes "Role of mRNA Decay in the 07/15/04- 13,273 2,500 2% of Health Immune System" 06/30/09

Real-time FRET Core

Current Direct Costs 614,509Current Indirect Costs 261,960

TOTAL 876,469

169

SIDNEY PESTKA, M.D. (Continued)

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTSProgram Project - Full GrantNational Institutes "Role of mRNA Decay in the 07/15/04- of Health Immune System" 06/30/09 5,835,855 1,119,843.92

170

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

ARNOLD RABSON, M.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Activation of HTVL1 Gene Expression 12/07/01- 890,000 176,959 25% of Health and Oncogensis" 11/30/06

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

National Institutes "Cancer Center Support Grant" 03/01/00- 1,390,611 49,064 20% of Health 02/28/05 PI: Dr. W. Hait

National Institutes "Effects of TPA on 07/01/03- 1,107,160 0 10% of Health Leukemia and Solid Tumors" 03/31/07 PI: Dr. A. Conney

National Institutes "Training Program in 08/01/03- 985,621 0 5% of Health Translational Research in Cancer" 06/30/08 PI: Dr. E. Lattime

Current Direct Costs 226,023Current Indirect Costs 124,467

TOTAL 350,490

171

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

YACOV RON, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "A Gene Therapy Approach 9/15/2004- 647,500 323,750 30% of Health for the treatment of EAE" 05/31/08

Foundation of "A Gene Therapy Approach 07/01/04- 25,000 25,000 10% UMDNJ for the treatment of EAE" 06/30/05

Quigley Corporation "Assessment of anti-inflamatory 06/15/05- 12,000 12,000 0% properties of QR440" 06/14/06

Quigley Corporation "Assessment of protection 06/30/05- 25,000 25,000 0% from irradiation of QR336" 06/29/06

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Direct Costs 385,750Current Indirect Costs 179,682

TOTAL 565,432

172

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

YUFANG SHI, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Opioid-Mediated Fas Expression 11/01/01- 1,109,973 225,000 20% of Health in Lymphocyte Apoptosis" 06/30/06

National Space "Effects of Antiorthostatic Suspension 04/01/02- 616,702 213,680 15% Biomedical Research on the Immune System" 03/31/05 Institute

National Institutes "Regulation of RANKL Expression 7/15/2004- 992,826 187,003 15% of Health in T-Lymphocytes" 06/30/09

National Institutes "Role of mRNA Decay in the 07/15/04- 78,766 14,836 1% of Health Immune System" 06/30/09

Flow Cytometry Core

National Institutes "Role of mRNA Decay in the 07/15/04- 137,618 25,921 5% of Health Immune System" 06/30/09

Real-time PCR Core

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Dircet Costs 666,440Current Indirect Costs 373,530TOTAL 1,039,970

173

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

VICTOR STOLLAR, M.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

Foundation of "Master Educators' Guild" 07/01/04- 3,000 3,000 0% UMDNJ 06/30/05

Foundation of "Excellence in Teaching" 07/01/04- 1,000 1,000 0% UMDNJ 06/30/05

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Current Direct Costs 4,000Current Indirect Costs 0

TOTAL 4,000

174

RESEARCH GRANT SUPPORT 07/01/04 - 06/30/05

NANCY WOYCHIK, PH.D.

SOURCE TITLE AWARD TOTAL CURRENT EFFORTPERIOD DIRECT DIRECT

COSTS COSTS

National Institutes "Virus-Host Interactions in 09/30/91- 743,310 0 5% of Health Eukaryotic Cells" 08/31/08 Participating Faculty PI: Dr. S. Pestka

Takara Bio, Inc., Japan "Single Protein Production 06/01/04- 82,908 41,454 0% Collaborator in Yeast Cells" 05/31/06 PI: Dr. Inouye

Current Direct Costs 41,454Current Indirect Costs 0

TOTAL 41,454

175

Summary of Outside Grant Support

Year 93-94 94-95 95-96 96-97 97-98 98-99 99-00 00-01 01-02 02-03 03-04 04-05

NIH SUPPORT

Direct Costs 1,321,578 2,112,637 1,740,660 2,212,010 2,012,210 2,876,948 3,425,550 3,879,828 4,792,386 4,298,753 4,442,085 4269214Indirect Costs 604,722 691,679 655,237 850,309 820,359 1,118,200 1,399,058 1,510,981 2,045,795 1,783,612 1,686,718 1733160Total Costs 1,926,300 2,804,316 2,395,897 3,062,319 2,832,569 3,995,148 4,824,608 5,390,809 6,838,181 6,082,365 6,128,803 6,002,374

OTHER AGENCY SUPPORT

Direct Costs 1,993,417 2,003,935 1,601,499 1,182,561 1,259,004 1,243,032 1,372,096 1,194,170 1,569,626 1,778,429 1,558,139 1290775Indirect Costs 265,790 171,280 130,875 73,348 119,199 163,061 236,535 141,089 211,197 287,104 265,273 209,236Total Costs 2,259,207 2,175,215 1,732,374 1,255,909 1,378,203 1,406,093 1,608,631 1,335,259 1,780,823 2,065,533 1,823,412 1,500,011

TOTAL

Direct Costs 3,314,995 4,116,572 3,342,159 3,394,571 3,271,214 4,119,980 4,797,646 5,073,998 6,362,012 6,077,182 6,000,224 5,559,989Indirect Costs 870,512 862,959 786,112 923,657 939,558 1,281,261 1,635,593 1,652,070 2,256,992 2,070,716 1,951,991 1,942,396Total Costs 4,185,507 4,979,531 4,128,271 4,318,228 4,210,772 5,401,241 6,433,239 6,726,068 8,619,004 8,147,898 7,952,215 7,502,385

176

SEMINARS Date/Host 08/03/04 Dr. Zheng 10/26/04 Dr. Copeland 11/09/04 Dr. Brewer 11/30/04 Dr. Foran 12/07/04 Dr. Leibowitz 01/11/05 Dr. Shi 01/14/05 Dr. Pestka 02/08/05 Dr. Stollar 03/08/05 Dr. Woychik 03/12/2005 Dr. Copland 03/16/05 Dr. Dougherty

04/14/05 Dr. Dougherty 04/27/05 Dr. Li 05/10/04 Dr. Kinzy 06/14/05 Dr. Li

Speaker Kenneth B. Buck Thesis Defense Dr. Donna M. Driscoll Lerner Research Institute Dr. Myriam Gorospe National Institute of Health Wenjin Chen Thesis Defense Dr. Mary Konsolaki Rutgers University Dr. Patricia Morris Rockferrat University Jin Hyung Lee Thesis Defense Dr. John M. Taylor Fox Chase Cancer Center Dr. Joyce Bischoff Harvard Medical School Dr. Ray Burk Vanderbilt University Jianling Zhuang Thesis Defense Radharani Duttagupta Thesis Defense Danielle Frikker Thesis Defense Dr. Sandra Weller University of Connecticut Guohong Hu Thesis Defense

Title “Intracellular Mechanisms of Growth Cone Turning Responses: New Rolse for Microtubles and Cyclic Amp” “Translational Recoding of UGA as Selenocysteine” “Journey Matters: Ribonucleoprotein Partnerships Regulation mRNA Turnover and Translation” “Digital Microscopy & Computer-Based Image Interpretation for Investigative Research in Pathology” “A Drosophila model for Alzheimer’s beta amyloid-related toxicity” “Cytokines regulate the StARs: a tale of interleukins and START domain expression” “Identification & Characterization of Type II Protein Arginine Methyltransferases” “An Intriguing Story Linking 2 Hepatitis Visuses, c-myc, a Liver Tumor, and miR122, a Liver-Specific Micro RNA” “Endothelial Cell Growth and Differentiation in Hemangioma An Endothelial Tumor That Undergoes Spontaneous Regression” “Biological Activities of Selenoprotein P” “HIV-1 Recombination: Tools, Characteristics & Mechanistic Implications” “Modulation of mRNA stability by transacting factors in the yeast Saccaromyces cerevisiae” “Analysis of Human Meiotic Recombination & Haplotype Block Formation” “How Herpes Simplex Virus commandeers the host cell chaperone and DNA damage machinery” “Establishment of a high throughput and sensitive gene expression profiling system”

177

DEPARTMENT OFMOLECULAR GENETICS, MICROBIOLOGY

AND IMMUNOLOGY

DEPARTMENTAL RETREAT

The Hilton Garden Inn ! Bridgewater, New Jersey

Friday, August 27, 2004

Agenda

8:30 a.m. Continental Breakfast

9:00 a.m. Greetings - Dr. Sidney Pestka

9:10 a.m. Presentations - Yvette Green, Moderator

9:15-9:30 Mohan Liu (Dr. Nancy Woychik)Applications for Bacterial mRNA Interferases in Yeast Cells

9:30-9:45 Satish Devadas, Ph.D. (Dr. Yufang Shi)Apoptosis Modulates the Th1/Th2 Balance: Distinct Roles for Caspasesand Granzyme B

9:45-10:00 Alison Swaims (Dr. Arnold Rabson)Immunologic Characterization of HTLV-1 Tax Transgenic Mice

10:00-10:15 Chris Krause, Ph.D. (Dr. Sidney Pestka)Evolution of Class 2 Cytokine Receptors from Interferon Receptors andthe Development of Adaptive Immunity

10:15-10:30 Radha Duttagupta (Dr. Stuart Peltz)Target analysis of Pub1p in the yeast Saccharomyces cerevisiae

10:30-10:45 Danielle Frikker (Dr. Honghua Li)Direct Analysis of Meiotic Recombination in the Human Genome

10:45 - 11:10 a.m. BREAK

178

11:10 a.m. Presentations - Kristina Sutphen, Moderator

11:15-11:30 Raj Prasad, Ph.D. (Dr. Michael Leibowitz)Meiotic resetting of the [KIL-d] phenotype requires prior mating,regardless of ploidy

11:30-11:45 Stephane Gross, Ph.D. (Dr. Terri Goss Kinzy)Mapping the Location and Functional Consequences of the TranslationElongation Factor 1A-Actin Interaction

11:45-12:00 Sofiya Micheva-Viteva (Dr. Joseph Dougherty)A Model of HIV-1 Latency for Drug Discovery and Mechanistic Studies

12:00-12:15 Hector Caban (Dr. Paul Copeland)Functional Analysis of Factors Required for Selenoprotein Synthesis

12:15-12:30 Sandra Chesoni (Dr. Gary Brewer)Genome-scale Identification and cloning of human cardiac mRNAassociating with AUF1

12:45 p.m. LUNCH

179

Department of Molecular Genetics, Microbiology and Immunology

Joint Faculty Appt. (17)

Adjunct Faculty (28)

Rick Wernoski Business Mgr.

(5-4937) Walter Barnes Budget Analyst III

(5-4074)

Core Facility: Lab Assistant

Princ. Lab Asst. Lab Svc. Wkr.

Ellen Feibel Sr. Mgmt. Asst.

(5-5116)

Nancy Stevens Sec. I

(5-5457)

Charnel Bohn Admin. Analyst

(5-5456)

Gabby Dava Comp. Hard.

Tech. Supp. III (5-4832)

Toni Thomas P/T Sec. IV

(5-4568) Rosalie Reina Program Asst.

(5-4154)

Student Assistant (5-4831)

Sidney Pestka, Chairman & Professor (5-4567)

J. Dougherty Professor (5-4588)

D. Dubin Professor (5-4643)

T. Kinzy Professor (5-5450)

M. Leibowitz Professor (5-4795)

S. Peltz Professor (5-4790)

Y. Ron Professor (5-5284)

Y. Shi Professor (5-4501)

P. Copeland Asst. Professor

(5-4670)

J. Langer Assoc. Professor

(5-5224)

H. Li Assoc. Professor

(5-7330)

N. Woychik Assoc. Professor

(5-4534)

V. Stollar Professor (5-4596)

J. Cook Adj. Asst.

Prof (5-4833)

M. Li Adj. Asst.

Prof (5-5449)

M. Newlon Asst. Prof (5-5448)

S. Sarkar Adj. Asst.

Prof (5-4826)

L.A. Schein Adj. Inst. (5-3446)

H-Y. Wang Adj. Asst.

Prof (5-8056)

J. Xie Adj. Asst.

Prof (5-4830)

GS (6) RTS (2)

Lab Asst (1)

GS (5) RTS (1)

GS (3) RTS (3)

Lab Tech (1) GS (1) PD (2)

RTS (6)

Postdoc (1) RTS (1)

GS (2) RTS (2)

GS (3) RTS (5) RA (1)

RTS (2)

GS (1) Postdoc (1)

RTS (7) Lab Asst (1)

GS (2)

GS (2) RTS (4)

G. Brewer Professor (5-3473)

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