DIVISION OF NEPHROLOGY

CHILDREN’S HOSPITAL BOSTON300 LONGWOOD AVENUE

BOSTON, MA 02115

COMMUNICATION WITH PROGRAM

We have received your letter expressing interest in the fellowship program atChildren’s Hospital Boston. Enclosed is a brief summary of our currentactivities. We strongly recommend that you come for an interview. Mostapplicants have found that this interview is extremely helpful in clarifyingour training program and our clinical and research facilities.

We will be happy to discuss all aspects of the training program with you.Please feel free to contact us at:

Office: (617) 355-6129Fax: (617) 232-4315

David M. Briscoe, M.D.Co-Director, Training Program in Pediatric NephrologyAssociate Professor of PediatricsHarvard Medical SchoolE-mail: David.Briscoe@childrens.harvard.edu

CURRENT STAFF AND FELLOWS

STAFF

William E. Harmon, M.D.Chief, Division of Nephrology

John T. Herrin, MBBS, FRACPDirector, Dialysis Unit

Mohamed Sayegh, M.D.Director of Research

Michael J.G. Somers, M.D.Director, Clinical Services

Michelle A. Baum, M.D,Assistant in Medicine

David M. Briscoe, M.D.Associate in Medicine

Markus Frank, M.D.Assistant in Medicine

Indira Guleria, Ph.D.Assistant in Medicine

Jordan Kreidberg, M.D., Ph.D.Assistant in Medicine

Nader Najafian, M.D.Assistant in Medicine

Thomas Natoli, Ph.D.Assistant in Medicine

Soumitro Pal, Ph.D.Assistant in Medicine

Elahna Paul, M.D., Ph.D.Assistant in Medicine

Nancy M. Rodig, M.D.Assistant in Medicine

Asher Schachter, M.D.Assistant in Medicine

FELLOWS

Reza Abdi, M.D. Stefan Kiessling, M.D.Steven Arora, M.D. Armen Margaryan, M.DGwenola Boulday, Ph.D.Nibedita Chattopadhyay, Ph.D.Xing Chen, M.D.Michael Clarkson, M.D.Jesse Flaxenburg, M.D.Xiaobo Gao, Ph.D.Zdenka Haskova, M.D., Ph.D.Brian Hershenfield, M.D.Jamie Imitola, M.D.Atsushi Izawa, M.D.Reshma Kewalramani, M.D.

Stuart Robertson, M.D.Sigrid Sandner, M.D.Charlie Szekeres, Ph.D.Avram Traum, M.D.Cynthia Wong, M.D.Bing Zhu, M.D., Ph.D.

Mona Khurana, M.D.

DESCRIPTION OF TRAINING PROGRAM

The Nephrology Division at Children’s Hospital Boston is currently the largestPediatric Nephrology division in the Untied States. One of the central goals ofthe Division is to develop academic Pediatric Nephrologists who will be able toestablish independent investigative careers in areas relevant to theunderstanding of childhood Nephrology diseases. The Fellowship Programprovides broad training in all the major areas of Nephrology with opportunitiesto develop clinical and research skills. There are three years of trainingcomposed of one clinical year and two years of laboratory research. TheTraining Program meets the requirements for certification by the Sub-board ofNephrology of the American Board of Pediatrics.

The clinical training year provides the Fellow with extensive exposure to awide variety of clinical problems in Pediatric Nephrology accomplished by fullparticipation of fellows in all the patient care activities within the Division.This includes the direct care of Nephrology inpatients, serving as consultantto both inpatient and outpatient divisional programs; as well as the care of thetransplant and pediatric dialysis outpatients and the general Nephrology clinicoutpatients. Fellows become proficient in all of the technical aspects ofNephrology such as performing renal biopsies, hemodialysis and peritonealdialysis. In addition, the Fellows acquire experience through the Departmentof Pathology in the interpretation of light, immunofluorescence and electronmicroscopy, and through the Department of Radiology in the interpretation ofuroradiologic studies.

The Division has two clinical services: the End-Stage Renal Disease Service(dialysis and transplantation); and the General Renal Consult Service. EachFellow spends approximately equivalent time on the End-Stage Disease andthe Consult Service. The fellow is responsible for: 1) supervising the care ofall inpatients who are followed by the Division of Nephrology; 2) providingconsultant services for Children’s Hospital Boston and the neonatal intensivecare unit at the Brigham and Women’s Hospital, Beth Israel DeaconessMedical Center, and other affiliated community hospitals; and 3) performingacute dialysis and hemofiltration as well as all percutaneous renal biopsies.

The two research fellowship years are a most important aspect of theFellowship Training Program and are aimed at broadening the Fellow’sunderstanding of renal disease. One of the unique aspects of our trainingprogram is the ability to participate in one of the many ongoing researchefforts in the Nephrology Research Laboratories. The Director of ourNephrology Research Program, Dr. Mohamed Sayegh and Dr. David Briscoeadvise Fellows in the selection of a basic science research projectapproximately six months prior to initiating the laboratory research fellowshipyears. Our laboratory research faculty share a common interest and expertisein cellular and molecular biology, immunology, renal development, glomerulardisease and transplantation biology. Research on the cell biology andtransport mechanisms present in epithelia of the kidney, lung, and cell of the

central nervous system are also interests within the faculty. We have aTransplant Immunology Research Program, focusing on mechanisms ofalloimmunity, functional interactions between lymphocytes and endothelialcells as well as immunologic tolerance. In addition, our renal developmentresearch program has a focused interest in the molecular regulation oforganogenesis. We are expanding our program in glomerular disease, whichcurrently is focused on the pathophysiolology of glomerulosclerosis. Also, aspecific interest of the clinical research faculty is the pathophysiology ofchronic Nephrology disease in children. Ongoing studies address growthabnormalities and defining risk factors influencing outcome of childrenundergoing chronic dialysis and transplantation therapies.

In general, the schedule is designed to promote optimal exposure to allaspects of Pediatric Nephrology during the training years. First year Fellowsare expected to prepare and present clinical conferences each month. Inaddition, Fellows actively participate in medical student teaching and houseofficer conferences. In subsequent years, the Fellow participates in theresearch conferences and makes periodic presentations of his/her researchefforts at individual laboratory as well as divisional research laboratoryseminars and journal clubs. Fellows also actively participate in medicalstudent teaching and house officer conferences. Lastly, all research fellowsare encouraged to attend Harvard seminars specific to their research interestincluding the Harvard Medical School Seminars in Immunology and VascularBiology.

Since very few pediatric Nephrologists can operate separately from anacademic institution or large affiliated medical center, our experience hasdemonstrated that all of these aspects of our training program are designed todevelop skills as a clinical scientist and teacher. We strongly believe that ourtraining program provides the opportunity to develop interests in all aspects ofthe clinical science of Pediatric Nephrology.

CLINICAL YEAR SCHEDULE

SERVICE TOTAL MONTHS

End-Stage 6.0Consult 5.5Vacation 0.5

WEEKLY SCHEDULEA. End-Stage Service: Transplant/Dialysis

1. Inpatient rounds and outpatient dialysis rounds: daily2. Transplant clinic: twice weekly3. Dialysis Conference: weekly4. Pre-transplant conference clinic: weekly5. Post-transplant conference clinic: weekly6. General Renal clinic: weekly7. Division research conference: weekly8. Clinical conference: weekly

B. Consult Service1. Inpatient rounds: daily2. Consults3. General Renal clinic: weekly4. Transplant clinic: weekly5. Division research conference: weekly6. Clinical conference: weekly7. Firm Rounds

CALL SCHEDULEA. First Year: every third weekB. Second Year: every sixth weekC. Third Year: no call

LICENSINGMassachusetts license

Annual Number of procedures performed in the Division are as follows:

RENAL BIOPSIES 110OUTPATIENT VISITS 3100INPATIENT CONSULTS (plus Nephrology patients) 700RENAL TRANSPLANTS 15-20ACUTE PERITONEAL DIALYSIS TREATMENTS 10-20ACUTE HEMODIALYSIS TREATMENTS 500HEMOFILTRATION PATIENT-DAY 100CHRONIC HEMODIALYSIS TREATMENTS 2500-3000CAPD-CCPD PATIENT-MONTHS 50-100

HISTORY OF FELLOWSHIP TRAINING AT CHILDREN’S

The central goal of the Pediatric Nephrology Fellowhip Training Program atChildren’s Hospital Boston has been to develop full-time academic PediatricNephrologists who establish independent investigative careers in areasrelevant to the understanding of childhood Nephrology diseases. Ourtraining program has expanded over the last 10 years and currently has twocomponents. The first component is the training of academic pediatricians inthe specialty of Pediatric Nephrology, including investigative biology and thebasic science pertaining to the pathophysiology of pediatric kidney disease.The second component of our program is to train scientists in the specialty ofPediatric Nephrology. Trainees who enter our program are exposed to a widevariety of individuals all dedicated to investigative Nephrology. Theseindividuals have backgrounds in many different specialties and includestudents, pre-doctoral and postdoctoral candidates as well as PhD's. Ourprogram ensures that all trainees work side by side which enhances theirmutual education and creates an environment for rigorous scientificinvestigation. Thus, our program is currently established for the training ofPediatric Nephrologists and for the advancement of biomedical research inthe specialty of Pediatric Nephrology.

Since its inception in 1974, our program has graduated a total of 50 fellowsfrom the Pediatric Nephrology fellowship program and is currently engaged inthe training of another 6. In addition, we are currently training another 18post-doctoral research fellows. Pediatric Nephrology trainees who graduatefrom our Program fulfill the criteria for certification in Pediatric Nephrology bythe American Board of Pediatrics and the specialty sections of the AmericanAcademy of Pediatrics. Graduates of our program include 2 DepartmentChairmen, 8 Directors of Pediatric Subspecialty Divisions and 11 Directors ofmajor research laboratories. In total we have trained at least 20independently funded, established biomedical investigators since theinception of the program and most of our trainees are full-time faculty atacademic pediatric hospitals or universities.

At the national level, many of our trainees have received awards for theirwork. For instance, of nine trainees who completed our program in 2002-03,six received awards related to their research studies. Over the past 5 years,many of our trainees received notable awards, including: two NIH NationalResearch Service Awards and one Pediatric Scientist Development Award.Also, several of our trainees who completed training within the past fiveyears have received NIH career development awards including three K08s,one K01 and one K23.

Graduates of our program are also identified as international leaders innephrology research. For instance, several (E. Avner M.D., A. Arnaout M.D.and T. Kon M.D.) have been members of NIH study sections, three (A.Krensky M.D., D.M. Briscoe, M.D. and W.E. Harmon, M.D.) are recognizedleaders in the field of kidney transplantation; one (L. Guay-Woodford, M.D.)is a leader in the field of inherited renal diseases; and one (S. Goldstein,

M.D.) is increasingly recognized as a major national authority in pediatrichemodialysis.

CURRENT FUNDED RESEARCH STUDIES WITHIN THEDIVISION

1. Mechanisms of Indirect Allorecognition and T Cell Co-stimulation in Acuteand Chronic Rejection in Experimental Animal Models

2. Autoimmune Responses in Primates

3. Immunorecognition in Chronic Allograft Rejection

4. Calcineurin Inhibitor Sparing Protocol in Living Donor Pediatric KidneyTransplantation

5. Nuclear Factor Kappa B in Pediatric Nephrotic Syndrome

6. Mechanisms of Chronic Rejection in Humans

7. The Role of T Cell Co-stimulation in Tolerance Induction in TransplantRejection and Autoimmunity

8. The Graft Vascular Endothelium in Chronic Rejection

9. Vascular Endothelial Growth Factor in Alloimmunity

10. Mechanisms of Islet Allograft Rejection and Tolerance

11. Angiogenesis and Chronic Rejection

12. The Effects of Sirolimus vs. Standard Treatment on Clinical Outcomes

13. Vascular Endothelial Growth Factor and Semaphorins in KidneyDevelopment

14. Vascular Endothelial Growth Factor and Renal Inflammation

15. Use of Rituxan in Pediatric Solid Organ Recipients with Post-TransplantLymphoproliferative Disorders

16. Vascular Endothelial Growth Factor in Acute and Chronic Rejection

17. Integrins in Kidney Epithelial Morphology

18. Integrin Cadherin Cross-Talk in Salivary Gland Development

19. Transgenic Organ Cultures

20. The Endothelium and Direct versus Indirect Allorecognition

21. B7 Blockade in Pediatric Renal Transplantation

22. Molecular Tools For Monitoring Immunosuppression Post-Transplantation

23. Training in Bioinformatics

24. Use of Artificial Intelligence to Monitor T cell activation andImmunosuppression efficacy.

25. Serum Cystatin C as a Marker of Glomerular Filtration

26. Oxidant and Antioxidant Levels in Children with Chronic RenalInsufficiency and End Stage Renal Disease

27. Prophylactic Urokinase Use in Hemodialysis Catheters

28. Genetic Control of Podocyte Function

29. Alternatively Spliced Form of CTLA-4 and Genetic Susceptibility to Type 1

30. Diabetes

31. A Double-Blind Randomized Trial of Steroid Withdrawal

32. Use of Amlodipine in Children with Hypertension

33. Development of Cystic Renal Disease in Native and Transplanted Kidneys

34. Use of Enalapril in Children with Hypertension

35. Use of Growth Hormone in Dialysis Patients

36. Probabilistic Modeling of the Drug Development Domain

37. P-glycoprotein Function in Allograft Rejection

38. Melanoma Tumor Growth Inhibition and Chemoresistance Reversal in vivoVia Targeting of a Novel Human Multidrug Resistance P-glycoproteinHomologue

39. Role of PD-1 in Type 1 Autoimmune Diabetes

FACULTY AT CHILDREN’S HOSPITAL BOSTON,DIVISION OF NEPHROLOGY

1) William E. Harmon, M.D., Associate Professor of Pediatrics, HarvardMedical School and the Director of the Division of Nephrology of Children’sHospital Boston, is the Training Program Director. Dr. Harmon’s clinical andresearch interests involve the pathophysiology and treatment of end-stagerenal disease (ESRD) in children. Dr. Harmon has extensive experience inrenal transplantation in children, especially infants and young children. Dr.Harmon is internationally recognized as a leader in pediatric organtransplantation. He served as the President of the American Society ofTransplantation (AST) last year and is currently its immediate PastPresident. He is also the Chairman of the Transplant Advisory Group of theAmerican Society of Nephrology and he serves on the Board of Directors ofthe International Pediatric Transplant Association (IPTA). Dr. Harmon’sprominence in Pediatric Transplantation led to his appointment as the firstChairman of the permanent Pediatric Committee of the United Network forOrgan Sharing (UNOS) and eventual membership on its Board of Directors.He is a member of the DHHS Secretary’s Advisory Committee onTransplantation (ACOT) and is the Pediatric consultant to the ScientificRegistry of Transplant Recipients (SRTR). Dr. Harmon’s particular interestpertains to immunosuppression to optimize successes following pediatricrenal transplantation and to the promotion of organ donation initiatives. Herecognized the need for multi-center trials to test pediatric hypotheses andthus, he was one of the earliest members of the North American PediatricRenal Transplant Cooperative Study (NAPRTCS). NAPRTCS was founded in1987 and since that time has accumulated information on over 15,000children with ESRD; this information has served as the basis for over onehundred manuscripts on all phases of treatment of CRI and ESRD. Dr.Harmon published the first analytical study from the NAPRTCS database andhas been involved in most of its subsequent studies. He was named thePresident of NAPRTCS last year and has launched an important restructuringof the organization. Importantly, he developed the studies and protocols thatwere subsequently used as the basis for the development of the CooperativeClinical Trials in Pediatric Transplantation (CCTPT), which is sponsored by aU01 mechanism of the NIH. These trials, which have been ongoing for thepast nine years, have been extremely productive and have been the basis ofnew techniques for provision of renal transplantation to children. One of themost innovative components of these studies is the description and analysisof intragraft gene expression of informative molecules. Dr. Harmon hadcollaborated with Dr. Terry Strom of the Beth Israel Deaconess MedicalCenter in the first description of these techniques in 1992. Subsequently,these techniques have formed the basis for defining the immune process inorgan transplantation. Dr. Harmon is currently the Principal Investigator ofthe two multi-center clinical trials supported by CCTPT and serves asChairman of its steering committee. Dr. Sayegh, the Research Director ofthe Division, serves as Co-Principal Investigator of the grant and he is incharge of coordinating the mechanistic and immunologic studies of studysubjects. In addition to these scientific studies, Dr. Harmon has becomeactively involved in issues concerning organ donation and allocation, aboutwhich he has published multiple articles. He served as the Chairman of theBoard of Trustees of the New England Organ Bank, one of the largest organprocurement organizations in the United States. He served as Chairman ofthe AST Public Policy Committee and, as noted above, he is currently the

only Pediatric specialty member of ACOT. Dr. Harmon also has extensiveexperience in the elements of pediatric dialysis, specifically urea kineticmodeling to monitor and prescribe hemodialysis treatments for children. Hedesigned and directed the US multi-center trial of recombinant humanerythropoietin in children undergoing chronic dialysis. Dr. Harmon hasserved on several NIH Study Sections evaluating and promoting transplantand dialysis research. He is one of the editors of Pediatric Nephrology, theonly comprehensive textbook in the field. He is also an editor of PediatricSolid Organ Transplantation. Dr. Harmon is an Associate Editor of thejournal, Pediatric Transplantation.

Throughout his clinical and academic career, Dr. Harmon has beenactively engaged in education. He has been involved in the clinical trainingof every Pediatric Nephrology Fellow at Children’s Hospital Boston since hisappointment as the Director of the Dialysis Program in 1979 and as MedicalDirector of the Renal Transplant Program in 1984. He was appointed Directorof the Division of Nephrology in 1987 and assumed the directorship of theFellowship Training Program and the Nephrology training grant at that time.He has engaged in individual sponsorship of clinical studies with over 50% ofthe fellows since he became Director of the Fellowship Training Program in1987. Based upon these experiences, he has been asked to serve in advisoryroles for other training programs. He has been a member of the ResidencyTraining Committee and was one on the principal architects of therestructured Resident and Fellow Education Programs at Children’s HospitalBoston. He participated in the first Fellows’ Conference of the AST andserved as Chairman of its Training and Manpower Committee. When heassumed Directorship of the Pediatric Nephrology Training Program atChildren’s Hospital Boston, the program had been established butrecruitment and training of fellows was unequal from year to year. Hestabilized the program, assured that the program became vigorous and highlycompetitive, developed the first overall curricula and formed collaborationswith neighboring institutions. He has been very successful in recruiting allof the biomedical scientists who now form the core of the Division ofNephrology Research Laboratories that form the basis of the researchcomponent of the Pediatric Nephrology Fellowship Training Program.

In summary, Dr Harmon is an established local, national andinternational leader in the field of Pediatric Nephrology. He remainsdedicated to the training of future leaders in the field and has established aprogram at Children's Hospital Boston that will serve that purpose.

2) David M. Briscoe, M.D. [Training Program Co-Director], AssociateProfessor of Pediatrics, Harvard Medical School: Dr. Briscoe's researchinvolves detailed analysis of the mechanisms by which lymphocytes andendothelial cells interact with one another in the process of cell-mediatedimmune inflammatory reactions and allograft rejection. Studies involve theanalysis of molecules, intracellular regulatory pathways and cytokinesinvolved in the activation of T cells by endothelium. Dr. Briscoe’s laboratoryhas recently identified molecular pathways by which the endothelium canpromote both direct and indirect pathways of allorecognition. The hypothesiscurrently being tested is that the endothelium promotes the indirect pathwayof allorecognition and thus chronic allograft rejection. Dr. Briscoe’slaboratory has also identified that CD40-CD40Ligand interactions mediateVascular Endothelial Cell Growth Factor (VEGF) expression andangiogenesis, as they pertain to allograft rejection. The hypothesis beingtested is that CD40-CD40L interactions represent a link between thealloimmune response and angiogenesis, which facilitates the recruitment of

leukocytes into sites of inflammation, including allografts undergoingrejection. Dr. Briscoe has also investigated the role of VEGF- VEGF receptorinteractions in immune inflammation and has determined that VEGFreceptor mediated signals result in the expression of potent chemoattractantmolecules in endothelial cells. His current studies are evaluating how VEGFmight regulate chemokines and the relevance of VEGF-induced inflammationin alloimmunity.

3) Mohamed H. Sayegh, M.D., [Research Director], Associate Professor ofMedicine, Harvard Medical School: Dr. Sayegh’s major research interestsinclude the role and mechanisms of the "direct" and “indirect” pathways ofallorecognition in rejection and tolerance. In the so-called "direct” pathway Tcells recognize intact allo-MHC molecules on the surface of donor cells.Peptides, derived from endogenous proteins including MHC molecules, boundinto the groove of the MHC appear to play an important role in this mode ofallorecognition. In the so-called "indirect" pathway T cells recognizeprocessed alloantigen presented as allopeptides by self antigen-presentingcells (APCs). These allopeptides are derived from allo-MHC molecules or fromminor histocompatibility or tissue specific antigens. Dr. Sayegh hasdemonstrated that the indirect pathway occurs during allograft and xenograftrejection and plays an important role in the rejection process, especially inchronic rejection. His laboratory is currently focusing on studying thecontribution of indirect allorecognition to the rejection process includingestablishing a TCR transgenic animal which is specific to Class II MHCallopeptides. In addition, human studies in his laboratory are focusing ondeveloping novel assays to predict transplant outcome. Another majorinterest of Dr. Sayegh’s laboratory is investigating the role and mechanismsof T cell costimulation in transplantation and autoimmune diseases. Dr.Sayegh’s research studies focus on the role of CD28-B7 and CD40-CD40Lfamilies of costimulatory molecules in allograft rejection and autoimmunediseases, including diabetes. In addition, his studies focus on dissecting themechanisms by which blockade of these pathways may prevent acuterejection and induce long term allograft survival and tolerance, and preventand/or cure autoimmune diseases.

4) John Herrin, M.B.B.S. [Director of Dialysis Unit] Associate Professor ofPediatrics, Harvard Medical School: Dr. Herrin has long-standing experiencein natural history of renal diseases and especially in glomerular and tubulardisease. He has extensive experience in fluid and electrolyte balance in thecritically ill patient (ICU and extensive burns) and the design of transplantimmunosuppression in collaboration with the team at MassachusettsGeneral Hospital and through participation in NAPRTCS. Dr. Herrin has anactive interest in clinical research including studies on: a) autosomalrecessive polycystic disease, b) growth and development in the patient withchronic renal disease, c) the role of steroids in treatment of renal diseaseand, d) cytokine effects in nephrotic syndrome and focal glomerulosclerosisin transplant patients. These interests provide a strong background for amentorship role for fellows in training on the clinical services, including thegeneral consultation and end stage renal program. Dr Herrin also has a closeinvolvement in Harvard Medical School student teaching.

5) Jordan Kreidberg, M.D., Ph.D., [Director, Developmental BiologyResearch Laboratory], Assistant Professor of Pediatrics, Harvard Medical

School: Dr. Kreidberg’s research focuses on the signaling networks regulatedby transcription factors and adhesion molecules that control mammaliandevelopment. The Wilms’ tumor-1 tumor suppressor gene is a zinc fingertranscription factor required for development of the kidney and gonads. Acombination of transgenic and molecular biological approaches are beingused to understand its role in development and cancer. Transgenic miceexpressing mutant forms of Wt1 in kidneys have suggested that Wt1regulates the expression of growth factors that may regulate angiogenesisduring organ development. Thus, the hypothesis that the regulation ofangiogenesis has a crucial role in patterning developing organs is beingpursued in the laboratory. The laboratory has also devised technologies tomicroinject and electroporate gene expression constructs into embryonickidney organ cultures. This offers an alternate high-throughput means oftransgenesis to study fundamental regulatory networks that establishpattern formation during early organ development. a3b1 integrin is a memberof the integrin family of receptors. Similarly to how growth factor receptorstransduce signals to cells as a consequence of binding secreted growthfactors, integrins transduce signals upon interaction with components of theextracellular matrix. Thus, development and tumorigenesis are driven by theintegrated signaling from growth factor receptors and integrins. Mice carryinga targeted mutation of the a3 integrin gene exhibit abnormal development ofthe kidneys, lungs, skin and brain. Cadherins are a second group ofadhesion molecules that mediate cell-cell, as opposed to cell-matrix,interactions. The modulation of cadherin-mediated adhesion is of greatimportance in development and tumor progression. The laboratory is studyinghow integrin based signals regulate the function of the cadherin family ofcell-cell adhesion receptors to affect cell morphology. Based on thesefindings using in vitro systems, studies are proceeding to design transgenicand conditionally gene-targeted mice to test how integrin-mediatedregulation of cadherin function may affect development and tumorigenesis.

6) Michael Somers, M.D. [Clinical Director, Division of Nephrology],Assistant Professor of Pediatrics, Harvard Medical School: As ClinicalDirector, Dr. Somers is involved in all aspects of the clinical researchprogram. He has significant interactions with pediatric renal fellows on ourclinical service and has initiated several mechanistic studies with membersof our research training faculty. Dr. Somers has been involved in thetraining of many renal fellows and pediatric residents through his clinicalactivities. His active clinical and research interests include: a) thecharacterization of specific immune responses to E. coli in hemolytic uremicsyndrome; b) the role of vascular permeability factor (VPF, also known asVEGF) in the Nephrotic Syndrome and in the development of Focal andSegmental Glomerulosclerosis; c) bladder abnormalities in patientsundergoing renal transplantation; and, d) methods for the evaluation andmonitoring of continuous renal-renal replacement therapy in very youngchildren.

7) Michelle Baum, M.D. Instructor of Pediatrics, Harvard Medical School:Dr. Baum has a strong focus on teaching and the training of fellows inclinical Nephrology. In addition, Dr. Baum has several clinical researchinterests pertaining to her involvement with the Myelodysplasia Program atthe Children’s Hospital Boston. In this capacity, Dr. Baum has an interestin how bladder abnormalities might affect renal function and she is designinga registry to follow patients with myelodysplasia and assess factors that willpredict long-term renal dysfunction. Dr. Baum has participated in severalprojects with the North American Pediatric Renal Transplant Cooperative

Study (NAPRTCS) involving the affect of native renal diseases, particularlyFSGS, on renal transplant outcome. Dr. Baum is also involved in theanalysis of data from centers participating in the Prospective PediatricContinuous Renal Replacement Therapy registry. 8) Markus Frank, M.D., Instructor of Medicine, Harvard Medical School: Dr.Frank’s research interests concern the role of P-glycoprotein (P-gp) andrelated ABC transporters in immunity. Current projects in the laboratoryinclude: a) the analysis of a role for P-gp in the alloimmune response. Dr.Frank has recently defined a novel role for P-gp as a switch in dendritic cellvs. macrophage differentiation. b) the analysis of a novel, third human P-gpfamily member. Dr. Frank has cloned a novel P-gp family member, whichidentifies a rare, stem cell phenotype-expressing cell subset among primaryhuman melanocytes and malignant melanoma cells. This work involves acollaboration with the stem cell laboratory of Emanuela Gussoni of theGenetics department at Children’s Hospital Boston.

9) Nader Najafian, M.D , Instructor of Medicine, Harvard Medical School: Dr.Najafian’s major research interests include the development of clinicalrejection/tolerance assays in renal transplantation: There is a great deal ofinterest in the concept of developing one or more clinical assays formonitoring immune status of transplant recipients. The focus of Dr.Najafian’s research involves the use of monitoring assays to evaluatetolerance following transplantation. His laboratory is focused on developingdonor-antigen specific assays to measure alloreactivity. He has also beeninvestigating the role of regulatory CD4+CD25+ T cells in renal transplantrecipients: Dr. Najafian has demonstrated the existence of regulatoryCD4+CD25+ T cells in a cohort of human renal transplant patients. He iscurrently studying the role of these cells in renal transplant recipients andexploring the possibility to expand these cells ex vivo. He is also interestedin the role and mechanisms of T cell costimulation in transplantation andautoimmunity, with special focus on novel members of the B7-CD28superfamily including ICOS-ICOSL, as well as PD-1 and its ligands, PD-L1and PD-L2.

10) Thomas Natoli, Ph.D. Instructor of Pediatrics Harvard Medical School:Dr. Natoli’s research interest involves the role of Wt1 in renal developmentand in glomerular disease. Specifically, Dr. Natoli has generated Wt1-nullES embryonic stem cell lines and has used them to create chimeric mice forthe analysis of Wt1 expression in vivo. Current research projects involve: a)evaluation of Wt1 in gonadal development. Chimeric mice generated inlaboratory have demonstrated impaired spermatogenesis, with manyseminiferous tubules devoid of spermatogonia. These data suggest that Wt1is required in gonadal development. b) the role of Wt1 in glomerular-endothelial development. Dr. Natoli has generated transgenic mice that carrydominant-negative forms of the Wt1 gene under the control of the nephrinpromoter. This promoter drives expression in the podocytes, the site of Wt1expression in the adult kidney. Transgenic animals survived through E18.5,but were lost before weaning. E18.5 transgenic embryos demonstratedabnormalities of glomerular endothelial development. However, no change inexpression of podocyte structural proteins was observed. Ongoing studieswill address whether Wt1 regulates expression of angiogenic growth factorsthat play a role in glomerular endothelial cell development.

11) Soumitro Pal, Ph.D. Instructor of Pediatrics, Harvard Medical School:Dr. Pal’s research interests involve signal transduction pathways involved inangiogenesis. Current research projects include: a) An analysis of the rolesof oncogenes and protein kinases involved in the overexpression of vascularendothelial growth factor (VEGF), the most important angiogenic cytokine. b)The role of CD40 in angiogenesis. Dr. Pal has defined a novel CD40 induciblesignaling pathway that is functional in VEGF expression and VEGF-inducedangiogenesis. c) The role of VEGF-VEGF receptor interactions ininflammation. Dr. Pal has established that VEGF receptor-mediated signalsare of importance for the expression of chemoattractant chemokines thatfacilitate the trafficking of leukocytes into sites of inflammation.

12) Elahna Paul, M.D., Ph.D., Instructor of Pediatrics, Harvard MedicalSchool, Boston: Dr Paul’s research relates to the role of complement systemin immunity. She is currently using gene complement knockout andtransgenic mice in collaboration with Dr. Carroll to determine the effect ofthe complement system on early B cell development. She has developed aunique model for studying B cell tolerance by breeding C3, C4 and cr2knockouts with a B cell transgenic mouse. Dr. Paul is currently focusing herstudies on the effects of C4 defects on normal tolerization of autoreactive Bcells. These studies will be applied to our understanding of human renaldiseases in such as Lupus in which dysregulation of the complement systemis associated with autoimmune kidney disease.

13) Nancy Rodig, M.D., Instructor of Pediatrics, Harvard Medical School: Dr.Rodig’s research interest is memory T-cell endothelial cell interactions. Herresearch projects involve the isolation and characterization of murine cardiacmicrovascular endothelium and the analysis of the phenotype of T-cells inregard to the expression of negative novel costimulatory molecules. She hasalso investigated the function of the endothelium in T-cell activationresponses. She has recently begun clinical research studies involvingtranslational mechanisms related to the outcome and treatment of pediatricpatients with end-stage renal disease.

14) Asher Schachter, M.D., Instructor of Pediatrics, Harvard Medical School:Dr. Schachter’s research efforts focus on issues of Bioinformatics andartificial intelligence in pediatric renal disease. Dr. Schachter’s specificresearch focuses is to decipher the molecular mechanisms underlyingpediatric nephrotic syndrome (NS) using bioinformatic tools. Pediatric NS isthe most common glomerular disease in children and the most commonacquired disease causing renal failure in children. NS represents aheterogeneous group of disorders, many of which are immune mediated anddrug resistant. Therefore, this population of patients provides an excellentopportunity to study drug resistance at the molecular level, and to perhapsdevelop novel therapies. As well, of those children with NS who require renaltransplantation, many will lose their allograft to recurrence of NS, suggestingthat a systemic factor is pathogenic in this most severe subgroup of patients.Dr. Schachter’s research has provided some insight into the role of certaincytokines and transcription factors involved in NS. He is currently utilizinghigh-throughput techniques to study DNA, RNA and protein from NSpatients in order to develop molecular models of NS pathogenesis and drugresistance. In addition, the development of novel therapeutic agents fortransplantation benefits the pediatric NS population in thatimmunosuppressive agents have often been utilized off-label to treat steroidresistant NS and post-transplant recurrence of NS. To this end, Dr.

Schachter is focusing on transplantation genomics and decision analysis indrug development pertaining to immunosuppressive agents and the pediatricpopulation. Dr. Schachter’s informatics-related skills include facility inprogramming (Java, PERL, R, SQL) and analysis of high-throughput geneexpression data. Dr. Schachter is also experienced in the use of machine-learning models such as artificial neural nets and Bayesian networks tolearn from datasets and to build predictive models in transplantation andimmunology.

Faculty outside the Division of Nephrology:

1) Joseph Bonventre, M.D., Ph.D., Professor of Medicine, Harvard MedicalSchool, Boston: Dr. Bonventre is the Chief of the Renal Division at Brigham& Women’s Hospital. Dr. Bonventre’s major research interests are: a) therole of calcium, phospholipase A2 and lipids in signal transduction and cellinjury; b) Cellular and molecular mechanisms of ischemic injury, programmedcell death, and renal repair; and c) Kidney transcription factors-their role inrenal repair. Two proteins, KIM-1, an epithelial protein and nmb, amacrophage protein, are being studied to examine their roles in the responseof the kidney to acute injury. A Kim-1 knockout/Gal4 knock-in animal hasbeen derived to allow the use the promoter region of Kim-1 to expressproteins specifically in the S3 segment of the proximal tubule, where most ofthe injury occurs. Transcription factor studies focus on a novel kidney-specific zinc finger transcriptional repressor, Kid-1, whose expression isregulated in renal ontogeny and by ischemia/ reperfusion was cloned andcharacterized by the laboratory a number of years ago. The KruppelAssociated Box-A (KRAB-A) motif of this and other zinc finger proteins wasidentified as a common repressor motif. A transcriptional repressor, KRIP-1,that interacts with KRAB-A has been cloned. A new family of proteins thatassociate with KRIP-1 (Trip-Br family) have been characterized which interactwith E2F/DP1, two critical proteins for cell cycle regulation. This knowledgewill aid in the understanding of the role that PLA2s play in injury and lead tobetter insight into mechanisms important for gene regulation governing cellproliferation, cell death and tissue repair after acute renal failure.

2) Michael C. Carroll, Ph.D., Professor of Pediatrics and Pathology, HarvardMedical School: Dr. Carroll’s research interest is in the role of thecomplement system in innate and acquired immunity and how it links thetwo systems via cell surface receptors. His laboratory has recently found thatthe complement system is critical in marking antigens with an activatedfragment of complement C3 and in maintaining active self-tolerance in Bcells. Dr. Carroll’s approach to understanding the biological importance ofthe many interactions is by construction of genetic models. For example,using gene targeting, he has generated mice deficient in several of thecritical components, i.e. complement C3, C4 and receptors CR1 & CR2. Bygenetic reconstitution of these mice with transgenes bearing mutant forms ofthe protein or regulated by tissue specific promoters, novel insights into thecomplex complement system are being generated.

3) Michael Gimbrone, M.D., Professor of Pathology, Harvard Medical School:Dr. Gimbrone is the Chairman of the Department of Pathology at Brigham &Women’s Hospital. Dr. Gimbrone's research focuses on the mechanisms of

vascular disease, in particular the role of the endothelial cell in complexdisease processes such as atherosclerosis, thrombosis and inflammation.He was among the first to establish reproducible methods for the in vitroculture of endothelium and smooth muscle from human blood vessels and toutilize the tools of modern cell biology and molecular biology to dissect theirfunctions in health and disease. His laboratory has characterized thecytokine-activated endothelial cell as important in inflammation andatherogenesis. Most recently his group has focused on the molecularmechanisms linking biomechanical stimulation and endothelial generegulation in atherogenesis. Dr. Gimbrone has published more than 250research articles, book chapters and reviews in the field of vascular biology.He is a recipient of an Established Investigator Award from the AmericanHeart Association and the Warner Lambert/Parke Davis Award inExperimental Pathology (FASEB). He is a Past-President of the AmericanSociety for Investigative Pathology, the founding President of the NorthAmerican Biology Organization (NAVBO), and has served on the Board ofDirectors of FASEB, as well as various NIH study sections and nationaladvisory committees. In 1993, he received the Basic Research Prize from theAmerican Heart Association; in 1994, a MERIT Award from the National HeartLung and Blood Institute and an unrestricted Cardiovascular Research Awardfrom the Bristol-Myers Squibb Institute; in 1995, the Pasarow Award forResearch in Cardiovascular Diseases. In 1997, he was elected to theNational Academy of Sciences, and in 1999, to the American Academy of Artsand Sciences and the Institute of Medicine of the National Academy ofSciences. In 1999, he was a co-recipient (with Dr. Judah Folkman) of the J.Allyn Taylor International Prize in Medicine, recognizing his contributions tothe establishment of the field of vascular biology. He currently serves as theElsie T. Friedman Professor of Pathology at Harvard Medical School, Directorof the Center for Excellence in Vascular Biology at the Brigham and Women'sHospital, and Chairman of the Department of Pathology at the Brigham &Women’s Hospital in Boston, Massachusetts. One major focus of study inthe Gimbrone laboratory has been the molecular mechanisms that mediatethe localized interactions of leukocytes with the vascular endothelium atsites of acute and chronic inflammatory responses, and vascular injury andrepair. Our working concept has been that endothelium-dependentmechanisms (in particular, inducible cell surface adhesion molecules andsecreted cytokines/chemokines, such as IL-8 and MCP-1) are important localdeterminants of the spatial and temporal patterns of leukocyte-vessel wallinteractions. A second major focus of activity in the Gimbrone Laboratory(which has evolved from a long-standing collaboration with Prof. C.F. Deweyand colleagues in the Fluid Mechanics Laboratory at the MassachusettsInstitute of Technology) is the study of hemodynamic forces, such as wallshear stress, as modulators of vascular endothelial structure and function.Specially designed in vitro flow devices are used to expose culturedendothelial monolayers to defined laminar, disturbed laminar, and turbulentflow regimens, and the resultant morphological, biochemical and moleculargenetic changes are studied in the context of vascular adaptation, and alsothe pathogenesis of vascular diseases, in particular atherosclerosis. Finally,the Gimbrone Laboratory has undertaken a systematic approach to definingphenotypic modulation of vascular endothelium, in health and disease,utilizing state-of-the-art techniques for transcriptional profiling ofendothelial gene expression, in vitro and in vivo.

4) Julie Ingelfinger, M.D., Professor of Pediatrics, Harvard Medical School:Dr. Ingelfinger currently directs the Pediatric Nephrology Laboratory at theMassachusetts General Hospital. She recently stepped down as the Directorof Pediatric Nephrology at the Massachusetts General Hospital when she

joined the New England Journal of Medicine as an Associate Editor. Dr.Ingelfinger continues to work as a staff member and clinical PediatricNephrologist at the Massachusetts General Hospital. Her major researchinterest and the focus of her research involves the regulation and function ofintrarenal renin-angiotensin systems. Current projects in her laboratoryinclude: a) studies involving the intrarenal renin angiotensin system in therenal proximal tubule; b) the intrarenal renin angiotensin system indiabetes; c) the role of the renin angiotensin system in Fawn Hooded rats (amodel of focal glomerulosclerosis); and, d) the role of maternal nutrition inrenal development and the development of hypertension and mechanisms ofproximal tubule injury. In addition, Dr. Ingelfinger has strong collaborativeinteractions with Dr. Eric Grabowski, Pediatric Hematology-Oncology Servicein which she is studying the role of Shiga toxin in pathogenesis of thehemolytic uremic syndrome (HUS).

5) Raghu Kalluri, Ph.D., Associate Professor of Medicine, Harvard MedicalSchool: Dr. Kalluri’s research interest is the understanding of the role ofbasement membranes in kidney disease. Basement membranes arespecialized structures that are present in association with almost all celltypes in the human body. Current projects in Dr. Kalluri’s laboratory involve:a) An analysis of the structure of basement membranes with a specific focuson different isoforms of type IV collagen, laminin and proteoglycans thatbring about a unique tissue specificity; b) The analysis of glomerular andtubular basement membranes in the kidney and their relevance to manykidney diseases and fibrosis; c) An analysis of the molecular mechanismgoverning the progression of Goodpasture syndrome and Alport’s disease;and, d) The analysis of vascular basement membranes in angiogenesis. Thevascular basement membrane constitutes an important component of a bloodvessel and along with providing structural support, modulates capillaryendothelial behavior, especially during the sprouting of new blood vessels. These studies resulted in the discovery of five new basement membranes,which have anti-angiogenic protein fragments. Some of these proteinfragments are potent inhibitors of angiogenesis. e) The analysis ofhepatocyte drug metabolism using liver specific basement membrane andmatrices.

6) Isaac Kohane, M.D., Ph.D., Associate Professor of Pediatrics, HarvardMedical School: Dr Kohane, is the Director of the Children's Hospital BostonInformatics Program (CHIP) a multidisciplinary applied research and educationprogram at Children's Hospital in Boston. CHIP focuses on both bioinformaticsand clinical informatics. The faculty is diverse, including physicians withadditional training in information science and computer scientists withexpertise in the biological sciences. CHIP encourages collaboration and providesshared resources to develop innovative information technologies with the goal ofboth enhancing biomedical research and improving patient care. CHIP alsoserves as the bioinformatics core for several national genomics investigations.There are currently 15 CHIP faculty, nine CHIP fellows, five support staff and 3students. CHIP funding comes from multiple sources and collaborations,including NLM, NIHGR, NCI, NHLBI, NINDS, NIDDK, and NIAID. Web-based &downloadable bioinformatics resources created and maintained by CHIP includeSNPper, unCHIP, chipperDB, CAGED, BADGE, BEST, RelNet and CL-DNA(http://www.chip.org/chip2003/resources.cgi). CHIP bioinformatics researchendeavors include development of statistical and computational techniques foranalyzing gene expression data from microarrays under various experimentalsettings and for analyzing SNP (Single Nucleotide Polymorphism) data inperforming large-scale association studies. CHIP staff also develop tools tointegrate various databases effectively, and combine information from various

genomic and proteomic data to gain insights into biological pathways. DrKohane is also the Co-Director of the Harvard-MIT Division of Health Sciencesand Technology Bioinformatics and Integrative Genomics training program,funded by NHGRI. He is a co-author of a popular textbook, “Microarrays for anIntegrative Genomics” and an author on over 70 publications. Dr. Kohanesupervises many research projects within CHIP, including reverse engineeringof biological pathways, noise modeling of expression microarrays, geneclustering and classification, genomic applications to tumorigenesis, diabetesmellitus, neural development, and neuroendocrinology, personally controlledmedical record systems, distributed medical record systems, and automateddecision support.

7) Vijay Kuchroo, D,V,M, Ph.D. Associate Professor of Neurology, HarvardMedical School, Boston: Dr Kuchroos' major focus of research is theautoimmune T cell response. His research interests include the role ofcostimulatory molecules and their receptors in the induction anddifferentiation of T cells and regulation of autoimmunity. In addition, recentlythe laboratory has cloned novel cell surface molecules that are expressedexclusively on the surface of Th1 cells. One of the molecules appears to havea role in the macrophage activation and in mediating tissue destruction inautoimmune disease. The laboratory has primarily focused on studying the immune response toone of the major proteins of the CNS myelin namely myelin proteolipidprotein (PLP). By using peptide-MHC binding strategy, a number ofdeterminants in the PLP molecule that can induce an organ specificautoimmune disease, experimental autoimmune encephalomyelitis (EAE),have been identified. The T cell response to the encephalitogenicdeterminants of PLP in H-2 congenic mice has been analyzed, while somestrains of mice are highly susceptible, other H-2 congenic strains areresistant to the development of disease. Genetic basis for the diseasesusceptibility and resistance has been analyzed by identifying genetic loci bygenome wide scans, generation of congenic mice and identifying genesresponsible for the phenotype. T cell receptor (TcR) transgenic mice thatexpress TcRs that recognize various myelin antigens have also beengenerated in the laboratory and these mice develop spontaneousautoimmune disease on the susceptible but not on the resistant geneticbackground. The role of various costimulatory molecules and cytokines in theinduction and regulation of autoimmune responses is under activeinvestigation. We have previously demonstrated that the B7 costimulatorymolecules play an important role in the T cell differentiation. The mechanismby which costimulatory molecules affect T cell differentiation is not wellunderstood. Using yeast-two and yeast-three hybrid systems andintracytoplasmic tails of the costimulatory molecules, we have identified andcloned a number of novel molecules that may be involved in T celldifferentiation and effector functions.

8) Andrew H. Lichtman, M.D., Ph.D., Associate Professor of Pathology,Harvard Medical School: Dr. Lichtman’s research interests relate toleukocyte-endothelial cell interactions in cell-mediated immune reactionsand chronic disease. Current projects in Dr. Lichtman’s laboratory includethe immunobiology of endothelial cells. His studies involve the analysis offunctional interactions between the endothelium and T lymphocytes, the roleof endothelial cells in antigen presentation and costimulation of T cells, andselective recruitment of T cell subsets into inflammatory sites. He is alsoinvestigating immune mechanism in atherosclerosis. Particular emphasis ofhis studies focus on T cell responses to atheroma antigens, mechanism ofactivation of plaque T cells, and the recruitment of leukocytes into

atherosclerotic lesions. Dr. Lichtman is also undertaking studies of theactivation and effector functions of CD8+ T cell subsets cells in mousemodels of autoimmunity (myocarditis), tumor immunity, and transplantrejection.

9) Martin Pollak, M.D., Assistant Professor of Medicine, Harvard MedicalSchool: Dr. Pollack’s laboratory is working to identify genes involved in thedevelopment of focal segmental glomerulosclerosis (FSGS). FSGS is acommon form of renal disease, seen both as an isolated entity and as aconsequence of HIV infection, diabetes, obesity, and hypertension. Towardsthis goal, blood for DNA extraction and clinical analyses have been performedon members of approximately 90 families with an inherited form of thiscondition. The laboratory identified the first FSGS locus on chromosome19q13. This locus was subsequently refined and demonstrated geneticheterogeneity of FSGS. Using careful analyses of genomic sequencedatabases, it was possible to identify a number of candidate genes in theFSGS-1 interval. Mutations have recently been found in ACTN4, encodingalpha-actinin-4, in FSGS-1 linked families. Because FSGS is also a cause ofrenal dysfunction secondary to multiple other diseases, the laboratory isexamining the role of this FSGS gene as a candidate renal dysfunctionsusceptibility gene. Current efforts are underway to understand the functionof ACTN4 and the mechanism of this form of kidney disease using mousemodels and cell biologic approaches. Model organisms will be used to betterdefine the biology of the mutant protein. The laboratory is also working toidentify additional FSGS genes.

10) Terry Strom, MD, Director, Professor of Medicine, Harvard MedicalSchool: Dr. Strom is the Chief of the Immunology Division of the Beth IsraelDeaconess Medical Center. He has a long-standing interest in mechanismsof allograft rejection, the regulation of cytokine gene expression and tolerance induction. His research includes studies on transplant rejectionand tolerance induction. Using molecular techniques, the characteristics ofcells mediating rejection of grafts are under analysis. A focus of these studiesare the role of Th1 and Th2 cells, regulatory cells, specific cytokines/growthfactor requirements of lymphocytes and treatments that result in permanentgraft acceptance. Other studies of human renal biopsies evaluate molecularmarkers of acute rejection and predictors of chronic rejection. He is alsoinvestigating immunoligands, immunosuppression and gene therapy. Variousforms of IL-2, CTLA4, CD2 and IL-15 fusion proteins have been developed foruse as specific immunosuppressive agents. These agents are designed tointerfere with antigen-specific T cell activation by competitive inhibition ofcostimulatory signals or by targeted cell lysis. Studies are ongoing intransplantation experiments. Dr. Strom is also studying IL-15 receptorexpression. The laboratory has found that IL-15 receptors are inducible uponactivation mainly on T cells and macrophages. The effects ofimmunosuppressive drugs on IL-15 expression are currently being tested andpreliminary data suggests that the IL-15 pathway of T cell activation is ofimportance in rejection.

11) Vikas Sukhatme, M.D., Ph.D., Professor of Medicine, Harvard MedicalSchool: Dr. Sukhatme is the Chief of the Renal Division at Beth IsraelDeaconess Medical Center. Dr. Sukhatme's laboratory focuses on four majorareas: a) Renal Cell Carcinoma - A major program in the Sukhatmelaboratory concerns renal cell carcinoma. A gene known as von Hippel-Lindau(VHL) is altered in over 70 percent of renal cell carcinomas, and introduction

of a wild type copy into these cells abrogates tumorigenicity. The laboratoryhas identified three growth factors -- vascular endothelial growth factor(VEGF), transforming growth factor-alpha (TGF-a) , and TGF-ß - whose genesare repressed by the VHL product. This explains why these genes are oftenupregulated in renal cell carcinoma and may contribute to tumorigenicity.Signal transduction pathways connecting VHL to VEGF, TGF- a, and TGF-ßare under investigation. Other novel gene targets for VHL have also beenidentified by differential display. In vivo therapy directed at antagonizing theaction of TGF-ß suppresses growth of renal cell carcinoma. b) Anti-angiogenic Molecules and Mechanisms - A significant program in anti-angiogenic therapies in pre-clinical models of renal cell carcinoma is alsounderway. Soluble forms of endostatin, angiostatin, Kr5 and restin, a newlyidentified molecule, can now be produced in the laboratory, and theirintracellular mechanisms of action are under study. A Phase I clinical trialaimed at inducing an anti-angiogenic state in patients with advancedmalignancies but in good performance status is also underway utilizing acocktail of tPA and captopril. c) Somatic Cell Gene Therapy - Somatic cellgene therapy to the kidney is a new area of investigation in Dr. Sukhatme'slaboratory. Localization of a marker gene under different conditions ofinfection and in models of renal injury and disease are being assessed in thefirst phase of this work. Recently, vascular delivery in vivo has been achievedwith adenovirus. The focus is on chronic renal injury (anti-fibrotic strategies)and on the genetic modification of a kidney allograft. d) Kidney Development -Another effort in Dr. Sukhatme's laboratory is to define the molecular basisfor kidney development by characterizing a cascade of transcription factorsthat are critical in the induction of blastemal cells to form glomeruli andproximal and distal nephron segments. Studies have focused on a kidney-enriched transcription factor known as the Wilms' tumor suppressor geneproduct (WT1), which is necessary for kidney development. The WT1 gene wasisolated from a region homozygously deleted in a Wilms' tumor cell line,based on conservation of the DNA sequence in different species and onhybridization of the clone to kidney RNA, supporting its activity in the tissueof interest. Factors regulating expression of WT1 are being studied in cellculture and transgenic mice. DNAse I hypersensitive sites and scaffoldattachment regions have been identified in the WT1 gene locus, as an aid toidentifying critical cis regulatory elements.