the hospital for sick children healthier children. a better world

2005-2006 ANNUAL REPORT

THE HOSPITAL FOR SICK CHILDREN RESEARCH INSTITUTE Healthier children. A better world.

The Hospital for Sick Children Research Institute, Annual Report 05-064

research to improve the health of children everywhere

01 introduction 02 message from the chief of research 04 discoveries 05 awards & recognition 06 brain & behaviour research 08 cancer research 10 cardiovascular research 12 cell biology 14 developmental biology 16 genetics & genomic biology 18 infection, immunity, injury & repair research 20 integrative biology 22 lung biology 24 metabolism research 26 population health sciences 28 structural biology & biochemistry 30 research training 32 high-impact papers 34 technology & knowledge transfer 35 technology & knowledge transfer success stories 36 facilities 37 quick stats 38 fi nancials

contents

The Research Institute at The Hospital for Sick Children undertakes child-centred research across the life continuum from fetal origins to adult outcomes, including fundamental discovery, applied research, and outcomes and impact.

INNOVATION 2005-2006

introduction


dear friends,

After an all-inclusive strategic planning process, the hospital has a new vision for the future. It is very simple: Healthier children. A better world.

The Research Institute is committed to seeing that vision realized through internationally competitive and integrated initiatives linking research, clinical care and education.

We are implementing a new structure for the Research Institute that is designed to promote integration, innovation and research excellence. The current matrix structure with its 12 programs is being consolidated into seven research programs. These seven programs refl ect SickKids’ core research strengths, including fundamental discovery, applied research, and outcomes and impact research relevant to child health in its broadest sense. This planned reorganization will be implemented in September 2006.

Four leaders from the old programs will continue as program heads for the newly constituted programs. Three new leaders from within SickKids – one appointed on an interim basis – will lead the remaining programs. The programs are:

> Genetics & Genome Biology, led by Dr. Stephen Meyn (interim head) > Molecular Structure & Function, led by Dr. Lynne Howell> Physiology & Experimental Medicine, led by Dr. Martin Post> Cell Biology, led by Dr. William Trimble (newly appointed)> Developmental & Stem Cell Biology, led by Dr. Chi-chung Hui> Neurosciences & Mental Health, led by Dr. Michael Salter (newly appointed) > Child Health Evaluative Sciences, led by Dr. Teresa To

I would like to take this opportunity to thank the outgoing program heads, Drs. Sergio Grinstein, David Kaplan, Brian Robinson, Chaim Roifman, Johanna Rommens, Carter Snead and Fred Keeley for all their outstanding work over the past years in leading their programs and mentoring young scientists. Although they may be standing down as program heads, these leaders and others will be stepping up to help develop new hospital-wide interdisciplinary innovation centres, focusing on specifi c problems in

This is my fi rst annual report since taking on the position of Chief of Research of The Hospital for Sick Children (SickKids). My fi rst year at SickKids has been a busy and challenging one, getting to know the Research Institute and learning about the exciting science going on in so many different areas. We are now ready to implement some changes, building on the established excellence of the SickKids Research Institute, while better positioning us to be international leaders in children’s health research.

COLL ABORATIONFROM THE CHIEF OF RESEARCH

message

childhood health and disease. Criteria for establishing centres are being developed and we expect several new centres to be formed in the coming year.

Another signifi cant highlight this year has been the occupation of new research space in the Toronto Medical Discovery Tower (TMDT), which is located within the MaRS complex. Thanks to the efforts of Mary Jo Haddad, president and CEO of the hospital, the hospital’s Board of Trustees and SickKids Foundation, we were also able to secure lease of two additional fl oors at TMDT to be occupied October 2006. This development has provided much-needed space relief for our scientists and is also providing the fi rst opportunity in many years for signifi cant geographic consolidation of researchers with common interests and infrastructure needs. The development of the new space was enabled by a Research Hospital Fund grant from the Canada Foundation for Innovation and by funding from SickKids Foundation.

As always, research here in the SickKids Research Institute could not have happened without the support of provincial and federal government funding agencies, as well as charitable

disease-related foundations. We are also incredibly fortunate to be supported by the community through their donations to SickKids Foundation, donations that allow us to provide the best infrastructure, the most up-to-date equipment and the best people to make innovative research happen. The combination of philanthropic and grant support really works together to allow us to make great strides into children’s health research.

The excellent, committed scientists and the great administrative and operational support team in the institute and the hospital make it a pleasure to be Chief of Research. We’re looking forward to an exciting year in 2006-2007 with new discoveries, new partnerships and new transfer of knowledge to the betterment of children everywhere.

DR. JANET ROSSANTChief of ResearchThe Hospital for Sick Children

discoveries

Dr. Earl Silverman found that two arthritis

medications (methotrexate and lefl unomide)

commonly used in adults are safe and effective

in children.

Dr. Andrew Howard showed that playground

injuries among children were signifi cantly

reduced after the Toronto District School

Board removed hazardous equipment from

school playgrounds in 2000 and replaced it

with safer equipment.

Dr. Tilman Humpl found that the drug silde-

nafi l, also known as Viagra, may help children

suffering from pulmonary arterial hypertension.

Dr. Anna Taddio found that a new topical

anaesthetic (liposomal lidocaine 4% cream,

brand name Maxilene) effectively reduced pain

for children having IVs inserted (cannulation)

in the Emergency Department and improved

procedural success rates.

Dr. Sylvain Baruchel discovered a mechanism

of tumour cell survival in a hypoxic environment,

which may lead to new treatment options for

patients with neuroblastoma. Tumour hypoxia

is a lack of oxygen to the tumour. It contributes

to drug resistance and angiogenesis (formation

of new blood vessels), which ultimately lead to

tumour aggressiveness and treatment failure.

Drug resistance and angiogenesis are two

important pillars of failure to treat neuroblastoma.

Dr. Sean Egan and colleagues at Princess

Margaret Hospital showed that two genes,

Notch1 and Jagged1, are linked to more

aggressive breast cancers and that patients are

less likely to survive the disease when these two

genes are highly expressed. Drugs are already in

development to target the genetic pathway.

Dr. Gideon Koren and Motherisk researchers

determined that women being treated for

multiple sclerosis with beta interferon therapy

have increased risks of miscarriage or low

infant birth weight.

A study published by the Cleveland Clinic and

Dr. Ron Laxer provided the medical community

for the fi rst time with specifi c guidelines for

treating juvenile idiopathic arthritis, previously

known as juvenile rheumatoid arthritis, a

condition that affects approximately one

in 1,000 children.

A team of researchers led by Dr. Maru Barrera

found that children who survive cancer have

almost twice the rate of educational and social

problems compared to children without a

history of cancer. Children with brain tumours,

leukemia or neuroblastoma, and children

treated with cranial radiation therapy, are at

greatest risk for educational diffi culties and

social isolation.

Subtle differences in genes other than the

defective CFTR (cystic fi brosis transmembrane

conductance regulator) gene known to cause

the disease cystic fi brosis (CF), can signifi cantly

modify the severity of CF, a large multi-centre

international study concluded. The study was

led by University of North Carolina at Chapel

Hill, Case Western Reserve University and

SickKids (Drs. Julian Zielenski and Peter Durie).

An international team of researchers led by

Drs. Benoit Bruneau, Chi-chung Hui and Gil

Gross discovered that the cardiac expression of

a gene called Irx5 controls the heart’s electrical

pattern. Alterations in the electrical pattern of

the heart lead to electrical disturbances in the

heart, a life-threatening condition called

cardiac arrhythmias.

By comparing the human genome with that

of the chimpanzee, man’s closest living relative,

Dr. Stephen Scherer discovered that chunks

of similar DNA that have been fl ipped in

orientation and reinserted into chromosomes

are hundreds of times more common in

primates than previously thought. These large

structural changes in the genome, called

inversions, may account for much of the

evolutionary difference between the two species.

They may also shed light on genetic changes

that lead to human diseases.

Ependymomas, tumours that occur in different

parts of the central nervous system, appear to

arise from subpopulations of stem cells called

radial glia cells, according to Dr. Michael

Taylor and investigators at St. Jude Children’s

Research Hospital. The discovery explains why

some identical-looking ependymomas are

actually distinctly different diseases.

A team of researchers led by Dr. David Kaplan

discovered a protein that is responsible for

shaping the nervous system.

A team of researchers led by Dr. Michael Salter

and Université Laval discovered a protein that

plays a major role in neuropathic pain. This

discovery paves the way for the development of

new diagnostics and treatments for chronic pain.

Dr. Anna Taddio found that intravenous

morphine used alone or with a topical

anaesthetic (tetracaine) effectively reduced levels

of pain in newborn infants undergoing insertion

of central venous catheters (central lines).

Dr. Clifford Lingwood and researchers at

Canadian Blood Services found a novel

molecule that may prevent many types of

HIV from infecting different kinds of cells.

Dr. Gideon Koren and researchers from

St. Michael’s Hospital calculated that the annual

cost of Fetal Alcohol Spectrum Disorder to

Canadians is upwards of $344 million a year.

Dr. Dennis Scolnik determined that humidity

is an ineffective therapy for the common

childhood ailment croup.

ACHIEVEMENTS 2005-2006


Dr. Benjamin Alman was the 2005 recipient

of the Clinical Research Society of Toronto

Senior Investigator Award for his work on

the molecular mechanisms responsible for

the deregulation of cellular growth control

in musculoskeletal tumours.

Dr. Brenda Banwell was selected as one of

Canada’s 2005 Top 40 Under 40. Canada’s Top

40 Under 40 is a national program that celebrates

Canada’s leaders of today and tomorrow,

and honours Canadians who have reached a

signifi cant level of success and achievement,

but have not yet reached the age of 40.

Dr. John Brumell was awarded the

Burroughs Wellcome Fund 2005 Investigators

in Pathogenesis of Infectious Disease Award.

He was selected as one of just 11 awardees

from an applicant pool of 123.

Dr. Peter Dirks was the 2005 recipient of the

George Armstrong-Peters Prize. The prize

is awarded to a young investigator who has

shown outstanding productivity during his

initial period as an investigator, as evidenced

by research publications in peer-review

journals, grants held and students trained.

Dr. Mark Henkelman was elevated to the

rank of University Professor, the highest

honour the University of Toronto accords its

faculty. University Professor appointments are

restricted to no more than two per cent of

active faculty at the University of Toronto.

Dr. Andrew Howard was the inaugural

recipient of the John Sharrard Memorial

Medal, presented by the British Society for

Children’s Orthopaedic Surgery. This medal

recognizes academic contributions to children’s

orthopaedics. Dr. Sharrard, for whom the

award is named, was one of the outstanding

orthopaedic surgeons of his generation.

Dr. Janet Rossant received the 2005 Michael

Smith Prize in Health Research, Canada’s

most prestigious health research award. The

Michael Smith Prize in Health Research is

awarded annually by the Canadian Institutes

of Health Research to an outstanding

Canadian researcher who has demonstrated

a high degree of innovation, creativity,

leadership and dedication in health research.

The Ontario Mental Health Foundation

presented Dr. Joanne Rovet with the Dewan

Award. The annual award is granted for original

and unique laboratory or clinical research that

has signifi cant bearing on mental health.

Dr. Robert Salter received the 2005 Award

from the Paediatric Orthopaedic Society of

North America in recognition of his many

contributions to the diagnosis and treatment

of children with developmental dysplasia of the

hip. This is the third award that Dr. Salter has

received from the society.

Dr. Anna Taddio was awarded a Canadian

Pain Society Early Career Award. The award

is presented annually to an individual with

outstanding achievements within eight years

of completion of a doctoral degree or

post-fellowship qualifi cation.

The Canadian Institutes of Health Research

Institute of Musculoskeletal Health and

Arthritis presented Dr. James Wright with

a Quality of Life Research Award for his

research in gender disparity in knee and

hip joint arthroplasty surgery.

Canada Research Chairs

This past year, six more SickKids researchers

received new Canada Research Chairs (CRCs)

and one SickKids researcher had his chair

renewed. This brings the total of CRCs

housed at SickKids at year-end to 28.

> Dr. Benjamin Alman – Canada Research

Chair in Vascular and Metabolic Biology

(renewal)

> Dr. Gabrielle Boulianne – Canada Research

Chair in Molecular and Developmental

Neurobiology

> Dr. Lynne Howell – Canada Research Chair

in Structural Biology

> Dr. Michael Moran – Canada Research

Chair in Molecular Therapeutics

> Dr. Norman Rosenblum – Canada Research

Chair in Developmental Nephrology

> Dr. William Trimble – Canada Research

Chair in Molecular Cell Biology

> Dr. Shoshana Wodak – Canada Research

Chair in Computational Biology

and Bioinformatics

Canadian Academy of Health Sciences

Dr. Manuel Buchwald and Dr. Robert Salter

were elected to the position of Fellow of the

Academy of The Canadian Academy of Health

Sciences (CAHS), an organization whose pri-

mary role is to provide advice on and assess

key issues relevant to the health of Canadians.

Election to fellowship in the CAHS is consid-

ered one of the highest honours for individuals

in the Canadian health sciences community.

Endowed Chairholder Appointed

Dr. Janet Rossant – Holder of the Lombard

Insurance Chair in Paediatric Research at The

Hospital for Sick Children

Ontario Ministry of Research & Innovation

Early Researcher Awards

The Early Researcher Award (ERA) program

aims to help promising, recently appointed

Ontario researchers build their research teams

of graduate students, postdoctoral fellows

and research associates. Recipients of ERAs

at SickKids were:

> Dr. Nicola Jones

> Dr. Sheena Josselyn

> Dr. Colin McKerlie

> Dr. Lisa Robinson

> Dr. Chetankumar Tailor

Royal Society of Canada

The Royal Society of Canada, the Canadian

Academy of the Sciences and Humanities,

added three more SickKids researchers to its

ranks, awarding them the title of Fellow of the

Royal Society of Canada. Election to the Royal

Society of Canada is the highest honour that

can be attained by scholars, artists and scientists

in Canada.

> Dr. Mark Henkelman

> Dr. Freda Miller

> Dr. Michael Salter

awards & recognition


brain & behaviour researchNEUROPATHIC PAIN GENETICS OF ADHD

NEUROPATHIC PAIN Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Many people suffering from neuropathic pain appear normal but are in agony, experiencing lightning-like pain known as allodynia. This type of pain can alter perception to a point where previously innocuous or even pleasurable stimuli applied to the skin or tissues become extremely painful. Neuropathic pain may be experienced after nerve injury or from diseases that affect peripheral nerve function, such as diabetes, shingles or cancer.

After a peripheral nerve injury there is a biophysical change in spinal cord cells known as microglia. Microglia are typically considered to be immune cells in the nervous system, but have now been proven to be involved in neuropathic pain. Dr. Michael Salter knew that microglia had to communicate with nerve cells in the pain-processing network in the spinal cord. However, the mechanism for this communication was not known. Working with colleagues at Université Laval, it was discovered that the microglia talk to the nerves cells by releasing brain-derived neurotropic factor (BDNF). When BDNF was injected into the spinal cords of normal mice it resulted in allodynia. When the team made manipulations to block or intercept BDNF signalling from the microglia in the nerve-injured mice, the allodynia was reversed.

Effective pain diagnosis is a challenge to developing effective pain therapeutics. The gold standard for diagnosing neuropathic pain is a patient history and physical examination. However, many want objective proof that something is pathophysiologically different. As such, the team hopes to develop a probe that can measure the response of microglia in people with peripheral nerve injury. The team is also looking for ways to devise new kinds of therapeutics, as there is not presently any effective treatment for neuropathic pain.

GENETICS OF ADHD Attention defi cit hyperactivity disorder (ADHD) is a common psychiatric disorder of childhood. There is a strong genetic contribution and it is suspected that many genes may be involved, with only a small percentage identifi ed thus far. In Dr. Cathy Barr’s lab alone, 11 genetic risk factors have been identifi ed that can contribute to the onset of ADHD. Dr. Barr and colleagues tested specifi c candidate genes from the dopamine and serotonin systems and screened a number of candidate genes for DNA changes that may contribute to the genetic predisposition to neuropsychiatric disorders.

In one particular study, Dr. Barr and researchers from 13 laboratories around the world confi rmed the identifi cation of one gene in the dopamine system that is involved with ADHD. They discovered a much higher incidence of a specifi c marker in the dopamine receptor D5 gene transmitted from the parents in diagnosed children. This, along with the identifi cation of other genes, confi rms there is a genetic component involved in ADHD and begins to shed light on the mechanism by which symptoms occur.

If family members and teachers know there is a genetic predisposition to developing ADHD, symptoms may be recognized earlier. Once identifi ed, families with a child with ADHD can develop strategies to help themselves and their children manage the symptoms and develop effective learning strategies. Early detection and management is key in creating positive outcomes and reducing the chances for patients with this disorder to fall into negative patterns of low self-esteem, poor academic performance, addiction and isolation. While researchers have not yet developed a diagnostic genetic test for ADHD, these fi ndings provide parents of children with ADHD support against implications that bad parenting is the cause of the condition. Previously, these parents have had to live with rejection and criticism of their parenting skills. This research sheds light on the real causes of ADHD and will improve the lives of children with ADHD and their families.

mind & matter

SCIENTIFIC STAFF

Head & Senior ScientistDr. O. Carter Snead III

Senior ScientistsDr. Cathy Barr Dr. Maureen DennisDr. Robert HarrisonDr. Zhengping Jia

Dr. Maureen LovettDr. Joanne RovetDr. Michael SalterDr. Russell SchacharDr. Rosemary Tannock Dr. Margot Taylor Dr. Lu-Yang Wang

Scientist

Dr. Agnes Wong

Scientist-Track InvestigatorsDr. Karen Gordon Dr. Anne Marie Guerguerian Dr. Daisy Joo

Senior Associate ScientistsDr. James Drake Dr. Katharina Manassis Dr. Patricia McGrath Dr. Carol Westall

Associate ScientistsDr. Brenda Banwell Dr. Donald MabbottDr. Blake Papsin Dr. Mary Lou Smith Dr. Jiri Vajsar Dr. Jing Xiang


BRAIN TUMOUR PROGNOSIS AND TELOMERASE Cancer is a disease in which cells continuously divide and overcome death signals. One explanation for this behaviour is that cancer cells, unlike normal cells, contain a protein called telomerase. In the presence of telomerase, shortening of the chromosome does not occur and continual cell division is maintained. Each time a normal cell divides, its chromosomes, which contain the cell’s genetic material, divide as well and their ends, known as telomeres, will shorten slightly. After many generations of cell divisions, the chromosomes eventually shorten to a point that is not compatible with cell survival, and division no longer occurs.

Dr. David Malkin and his research group, including Dr. Uri Tabori, a clinical research fellow, investigated the telomere length in low-grade gliomas, a common type of childhood brain tumour. Low-grade gliomas are generally slow-growing, non-invasive, non-metastatic tumours that carry a much better prognosis than their fast-growing, highly invasive, potentially metastatic, high-grade glioma counterparts. High-grade gliomas almost always grow back even after complete surgical excision, radiation therapy and chemotherapy. Conversely, low-grade gliomas can often be observed for years without requiring treatment. Dr. Malkin and his group discovered the reason low-grade gliomas are low-grade is because they lack the telomerase enzyme and their telomeres shorten over time, thus limiting their growth potential. This observation provides an opportunity for clinicians to use this prognostic marker to eventually predict how long the tumour may continue to grow.

The research team also took its knowledge of telomerase and studied highly aggressive brain tumours called ependymomas. Using a tissue array system and integrating the microarray expertise of Dr. Cynthia Hawkins, the team measured the telomerase expression in a large number of ependymomas and discovered that tumours with low expression of telomerase had a better outcome than those expressing high amounts of telomerase.

Identifi cation of new biological prognostic markers may help to predict when use of those treatment options is most appropriate. Further, the fi nding that telomerase is so important in the aggressive behaviour of some ependymomas makes it a potential target for new treatment development.

TUMOUR HYPOXIA Tumour hypoxia is a lack of oxygen to a tumour. It contributes to drug resistance and angiogenesis (formation of new blood vessels), which ultimately lead to tumour aggressiveness and treatment failure. Drug resistance and angiogenesis are two important pillars of failure to treat neuroblastoma, a childhood tumour originating from the peripheral nervous system.

Drs. Sylvain Baruchel and Herman Yeger studied two signalling pathways in neuroblastoma in animal models and found that two proteins, MAPK (mitogen activated protein kinase) and HIF-1alpha (hypoxia-inducing factor-1alpha), were linked to drug resistance and angiogenesis. They found that both pathways are activated by an angiogenic growth factor called VEGF (vascular endothelial growth factor). During hypoxia, VEGF interacts with HIF and MAPK leading to both drug resistance and angiogenesis. Drs. Baruchel and Yeger also showed that by targeting the VEGF pathway in vitro with antibodies against VEGF or a molecule such as ursolic acid, the hypoxia-mediated drug resistance could be reversed and angiogenesis could be modifi ed in animal models. This work gives new insight into the hypoxia-related tumour aggressiveness and treatment failure in neuroblastoma, and suggests that anti-VEGF drugs may be helpful in treating neuroblastoma patients.

This fi nding is the fi rst step in the development of a new strategy to target tumour cells living under hypoxic condition. Researchers have already found that ursolic acid, a molecule found in Indian holy basil, can reverse hypoxia-mediated drug resistance and angiogenesis.

TUMOUR HYPOXIABRAIN TUMOURS

cancer research

SCIENTIFIC STAFF

Head & Senior ScientistDr. David Kaplan

Senior ScientistsDr. Helen ChanDr. Abhijit GuhaDr. Michelle LetarteDr. David MalkinDr. Michael MoranDr. James RutkaDr. Herman YegerDr. Rae Yeung

ScientistsDr. Brent DerryDr. Gregory HanniganDr. Meredith Irwin

Scientist-Track InvestigatorsDr. Cynthia HawkinsDr. Annie Huang

Senior Associate ScientistsDr. Sylvain BaruchelDr. Paul ThornerDr. Maria Zielenska

Associate ScientistDr. Mohamed Abdelhaleem

clues & cures

cardiovascular researchISCHEMIC PRECONDITIONINGHEART ARRHYTHMIA

TRANSCRIPTION FACTORS FOR HEART ARRHYTHMIA Normal electrical rhythms in the heart are essential to coordinate proper mechanical pumping action of the heart. Cardiac arrhythmias cause the heart to beat too fast, too slow or irregularly, leading to pump malfunction. Dr. Benoit Bruneau and Dr. Peter Backx of Toronto General Hospital discovered that the expression of the Irx5 gene in the heart is directly related to the occurrence of arrhythmias. Each time the heart beats, the electrical system that coordinates the heart must be repolarized, or reset, before the next beat. Drs. Bruneau and Backx showed that Irx5 is integral in this sequence of repolarization. The researchers explored the role of Irx5, which is a transcriptional factor, on electrical properties of the heart. Transcription factors are proteins that regulate other genes by turning them on or off. The research fi ndings showed that Irx5 is integral to controlling the number and distribution of selected types of ion channel proteins, like potassium channels, that are critical determinants of the heart’s normal electrical pattern.

Irx5 controls pathways in the heart that are key in keeping the heart arrhythmia-free. The Irx5 protein is expressed in different intensities on the interior and exterior of the heart, creating a repolarization gradient. The study found that in an animal model, this gradient is formed by Irx5 turning off ion channels on the inside layers of the heart. On the outside layers, Irx5 exists in much smaller quantities, keeping the ion channels open and creating the differential needed to repolarize the heart. When this differential is in the proper balance, the heart functions properly and the heart is kept arrhythmia-free. If the gradient is not working properly, then arrhythmias can occur. This study illuminated the function of the ion channel in repolarization. The next steps for the research group are to determine if Irx5 is implicated in heart failure or any other cardiac event where ion-channel signalling is affected.

REMOTE ISCHEMIC PRECONDITIONING Ischemic preconditioning is one of the most potent naturally occurring mechanisms of protection against tissue damage during periods of low blood fl ow. It is induced by making the target organ ischemic by reducing its blood supply for one to fi ve minutes, prior to a prolonged reduction in blood fl ow. Ischemia is a restriction in blood supply that can lead to damage or dysfunction of tissue.

Five years ago, Dr. Andrew Redington and colleagues showed that it was possible to precondition the heart and other organs against prolonged ischemia, by transiently reducing blood fl ow to a limb, using a simple blood pressure cuff or tourniquet. This simple manoeuvre reduced the size of a heart attack by more than 50 per cent in experiments, and is known as remote ischemic preconditioning. In studies of ischemic preconditioning of the heart, a brief stoppage of blood fl ow protects the heart against a subsequent much longer period of blood-fl ow cessation that occurs within an hour of the fi rst ischemic episode. Ischemic preconditioning enables tolerance against ischemic injury by pre-exposure of the heart to one or more brief episodes of ischemia. By preparing the heart for future ischemic episodes, like cardiac surgery, the heart is less susceptible to sustaining damage as a result of the procedure.

The research team has found that the heart and circulatory system could be put into a preconditioned ischemic state from a remote location in the circulatory system. Dr. Raj Kharbanda, a collaborator from the University of Cambridge, working on local preconditioning of the arm while investigating blood vessel dysfunction, noticed that you could condition one arm but have the preconditioned effects occur on the other arm. This remote preconditioning before heart surgery has been proven to reduce myocardial deterioration by 50 to 60 per cent. Using an animal model, it was discovered that this preconditioning protected the heart and lungs and also dramatically reduced post-operative infl ammation of these organs.

This fi nding was proven in a randomized clinical trial by former SickKids fellow and staff cardiologist Dr. Michael Cheung. Children with a blood pressure cuff-induced remote ischemic preconditioning had less lung and heart damage and reduced infl ammatory response after heart surgery. The children wore the cuff for 20 minutes before surgery began.

10 The Hospital for Sick Children Research Institute, Annual Report 05-06

heart & circulation

SCIENTIFIC STAFF

Head & Senior ScientistDr. Frederick Keeley

Senior ScientistsDr. John Coles Dr. Aleksander HinekDr. Gregory Wilson

ScientistsDr. Benoit BruneauDr. Gil GrossDr. Ian Scott

Senior Associate ScientistsDr. Andrew RedingtonDr. Steve SchwartzDr. Earl Silverman

Associate ScientistsDr. Christopher CaldaroneDr. Robert HamiltonDr. Edgar JaeggiDr. Shi-Joon Yoo


cell biologyINSULIN RESISTANCE CYSTIC FIBROSIS

INSULIN RESISTANCE Type 2 diabetes is an increasingly prevalent health problem among children and adolescents. The primary problem for those with the disease is resistance to insulin, a hormone that allows muscles to use dietary sugars (glucose) to produce energy for activity. For people with Type 2 diabetes, insulin-sensitive tissues lose the ability to respond correctly to insulin. The consequent accumulation of glucose in the blood results in a variety of complications, such as circulatory defects, blindness and cardiovascular disease. Glucose is the major fuel for most cells, and it is stored as glycogen in the liver and muscle tissue, as well as processed into fat. The liver provides the rest of the body, especially the brain, with glucose between meals. However, during a meal, insulin derived from the pancreas promotes glucose uptake into muscle and fat cells, and stops the liver from releasing glucose to the blood.

The mechanism whereby insulin increases glucose uptake into muscle and fat has received much attention, but molecular detail is still lacking. Dr. Amira Klip has been studying the mechanism of glucose uptake into muscle cells through glucose transporters or GLUTs, using cell biology and biochemical approaches to identify these entry ports for glucose, both for muscle cells and across the blood-brain barrier. Her work focuses on how a series of signal transduction pathways activated by insulin within muscle cells impact on intracellularly stored GLUT4, to move it to the cell surface. Her early work found that insulin causes this glucose transporter to move from inside the cell to the muscle plasma membrane, bringing glucose into the cell. In recent years, her team has identifi ed the participation of the cellular actin skeleton in such movement, and the requirement for membrane proteins involved in fusion. By clarifying the movement of GLUT4 and by defi ning which of the many steps involved in the process may be defective and potentially reversible in Type 2 diabetes, Dr. Klip and her lab hope to generate new approaches to combating insulin resistance and diabetes.

THE STRUCTURAL MATURITY OF CFTR Cystic fi brosis (CF) is a fatal genetic disease in which thick mucus clogs the lungs and the pancreas due to problems with the secretion of ions and fl uid by cells of the airways and gastrointestinal tract. Normal secretion depends upon the function of a protein called CFTR (cystic fi brosis transmembrane conductance regulator). Mutations in the gene encoding CFTR are responsible for cystic fi brosis. In the most common form of cystic fi brosis, the CFTR protein is trapped inside the cell, and is therefore unable to carry out its proper function at the cell surface. CFTR is made up of more than 1,400 amino acids and is organized into fi ve structural units or domains. The most common disease-causing mutation in cystic fi brosis patients is a single amino acid deletion at position 508 in the amino acid chain of CFTR. It was thought that this mutation disrupted the architecture of the fi rst domain and the protein from appearing at cell surface.

Recently, Dr. Gergely Lukacs and colleagues showed that the maturation of CFTR domains occur in a successive fashion. They also demonstrated that the amino acid positioned at the 508 location is essential for the structural maturation and stability of a second domain. Since the fi rst domain serves as structure for the maturation of the second one, the three-dimensional architecture of the fi rst domain, likely in concert with some other domains of CFTR, including the 508 amino acid, is key for the global folding of the CFTR channel. Without folding of the CFTR channel, the protein is confi ned to the cell and cannot function at the cell surface.This research suggests an intricate interaction among the domains of CFTR and that the loss of the 508 amino acid has devastating consequences on this interplay and consequently the structure of the second domain.

Using novel screening assays, the Lukacs lab participates in efforts to identify small molecules as potential drugs that rescue the foldingdefect of mutant CFTR. In collaboration with colleagues at Yale Medical School and the University of California San Francisco, the Lukacs lab has provided biochemical evidence for partial correction of the mutant CFTR processing by small molecules in cultured cells. The results have demonstrated that small molecules have the potential to be used for future drug development to alleviate the clinical symptoms in cystic fi brosis.

SCIENTIFIC STAFF

Head & Senior ScientistDr. Sergio Grinstein

Senior ScientistsDr. Amira KlipDr. Gergely LukacsDr. Jane McGladeDr. Daniela RotinDr. William TrimbleDr. David Bazett-Jones

Scientist-Track InvestigatorDr. Walter Kahr

Associate ScientistDr. Walid Farhat

Senior Scientist EmeritusDr. Aser Rothsteincause

& effect

developmental biologyEPENDYMOMASZEBRAFISH


ZEBRAFISH The zebrafi sh is a valued vertebrate animal model for studying human development and disease. It’s hardy, can be maintained in large numbers and is helping researchers discover the mechanisms behind development when it goes awry. Zebrafi sh embryos are transparent and laid externally, making them easy to screen, easy to watch as they develop, and no sacrifi ce is needed. The parents can mate again the next week, producing 100 to 200 embryos each time. Most remarkably, zebrafi sh enable live imaging of organ development and cell mitosis. Using a microscope, researchers can watch the 48-hour process of embryogenesis from fertilization to completion. This allows for imaging of the developing embryo at the cellular and sub-cellular level. As well, the opportunity to watch embryonic development in real time enables researchers to ask specifi c questions relevant to human development. Dysfunction of developmental processes in humans leads to problems like congenital heart defects and neural tube closure defects such as spina bifi da and anecephaly. Investigating these processes at the genetic and cellular level will help develop new means to treat and ultimately prevent these conditions from occurring.

Dr. Brian Ciruna revealed how a major cellular signalling pathway controls the formation of an embryo’s neural tube — its future spinal cord and brain. Correct polarity is essential for normal cellular function. During neural tube formation, if the pathway that regulates polarity is disrupted, the result is an open neural tube. Dr. Ian Scott uses the zebrafi sh model to study the mechanisms behind the formation of the vertebrate heart. Proper heart development requires the synthesis of a number of developmental processes. By screening through thousands of mutant zebrafi sh lines, he has isolated several novel mutations that affect the diverse steps of cardiac development. By taking advantage of the optical clarity of the zebrafi sh embryo, he will use these mutants to study the mechanisms that lead to congenital heart defects and how they may be prevented.

RARE STEM CELLS AT THE ROOT OF EPENDYMOMAS Ependymomas are the third most common central nervous system tumour in children and no effective chemotherapy exists for them. These tumours develop in various parts of the central nervous system, and are all clinically different, even though they look the same under a microscope. Although all ependymomas look alike, supratentorial ependymomas arise in the top part of the brain in both adults and children. They often cause weakness in the arms and legs, visual problems and seizures. Posterior fossa ependymomas arise in the back of the brain and cause patients to have an unsteady walk and neck pain. They occur mainly in children. Spinal ependymomas occur mainly in adults, and more than 70 per cent of patients who undergo surgery to remove this tumour survive.

While working as a postdoctoral fellow in the laboratory of Dr. Richard Gilbertson at St. Jude Children’s Research Hospital, Dr. Michael Taylor discovered that all of these ependymomas appear to arise from subpopulations of stem cells called radial glia cells. This discovery explains why some identical-looking ependymomas are actually distinctly different diseases. Demonstration that identical-looking ependymomas that arise in different regions of the central nervous system are distinct diseases at the cellular and molecular level suggests that treatments should be designed to kill the region-specifi c cancer stem cells. The different genetic signatures found in each subtype of ependymoma represent potential targets for new drugs designed to kill the regionally specifi c ependymoma cancer stem cells. Such individualized treatment might allow physicians to prevent the recurrence of ependymoma following treatment to remove the original tumour, by eliminating the cancer stem cells that give rise to the tumour.

different & similar

SCIENTIFIC STAFF

Head & Senior ScientistDr. Chi-chung Hui

Senior ScientistsDr. Benjamin Alman Dr. Gabrielle BoulianneDr. Jayne Danska Dr. Sean Egan

Dr. James Ellis Dr. Cynthia GuidosDr. Patricia Harper Dr. Howard Lipshitz Dr. Roderick McInnes Dr. Freda Miller Dr. Norman Rosenblum Dr. Janet Rossant

ScientistsDr. Julie Brill Dr. Brian Ciruna Dr. Peter Dirks Dr. Johann Hitzler Dr. Tino Piscione

Scientist-Track InvestigatorsDr. Priscilla Chiu Dr. Sevan Hopyan Dr. Jae Kim Dr. Michael D. Taylor

Associate ScientistDr. Christopher Forrest


genetics & genomic biologyFATES FOR DAMAGED DNADIABETES COMPLICATIONS

DIABETES COMPLICATIONS Diabetes is rapidly becoming one of the most serious health concerns for North American children. At last count, one in 300 Canadians has Type 1 diabetes and requires insulin injections for survival. While intensive insulin therapy can keep them functioning, it requires a lot of effort to return blood sugar levels to the normal range. Dr. Andrew Paterson is interested in determining the genetic connections between the complications that patients experience when they have diabetes. Are there genes that predispose a person to having kidney complications versus heart complications? The laboratory of Dr. Paterson uses population studies to identify genes that infl uence susceptibility to diabetes, as well as determine which genes affect the common complications that are seen from standard insulin treatment regimens. They performed this study using data from an international clinical trial performed across North America. Children with diabetes were followed, and their family histories and the histories of family members with diabetes were tracked, to look for any genetic or familial similarities in the type of complications they had.

From the study, they discovered a tendency for diabetic complications to be similar between relatives. The researchers took DNA samples from study participants and examined the angiotensin I converting enzyme (ACE) gene — a gene that controls the level of a chemical that regulates blood pressure. There existed previous evidence that variation in this gene leads to kidney complications. Dr. Paterson identifi ed a variation in the ACE gene that infl uences the susceptibility of kidney complications in Type 1 diabetes. Of 1,365 participants, a quarter had the low-risk variation of the ACE gene, whereas three-quarters had the high-risk variation of the gene. Some people were more vulnerable to kidney disease because they have a variation in the ACE gene. ACE is just one of many genes involved in genetic susceptibly to diabetes-related kidney complications. Dr. Paterson and his team are also looking for genes that relate to eye, heart and nerve complications associated with diabetes.

MULTIPLE FATES FOR DAMAGED DNA The human genome must replicate itself perfectly every time a cell divides. The integrity of the genome is guarded by DNA repair processes that can correct errors that are made during genome replication. At least 40 neurodegenerative and neuromuscular diseases are caused by mutations of certain repeated DNA sequences. These mutations cause diseases like Huntington disease and muscular dystrophy. Mutations in the DNA are not only passed on from parent to child, but continue to worsen in the patients during their life — underpinning the progressive nature of these diseases.

Dr. Christopher Pearson took a close look at the repair of a special type of genome segment, one that contains repeated trinucleotide sequences, and determined that the DNA repair processes may themselves be tricked, explaining why such trinucleotide sequences are prone to errors and lead to human genetic diseases. In affected families, these repeating DNA sequences can form unusual, slippery DNA structures. In some cases, these DNA structures form in the brain. These DNA structures need to be repaired or they can lead to mutations. However, Dr. Pearson and his group have found that the process of DNA repair can make the situation worse. Corrected DNA does occur in some types of tissue, but in many cases the result is error-prone repair that produces a mutation.

Knowing that there is more than one possible fate to repair DNA will help researchers identify the mechanisms behind correct or error-prone repair, or even how DNA can escape repair altogether. The next steps for Dr. Pearson and his research group involve determining what proteins are involved in these aberrant repair processes.

gene & sequence

SCIENTIFIC STAFF

Head & Senior ScientistDr. Johanna Rommens

Senior ScientistsDr. William ColeDr. Susanna LewisDr. Stephen MeynDr. Christopher PearsonDr. Stephen SchererDr. Lap-Chee Tsui

ScientistsDr. Berge MinassianDr. John ParkinsonDr. Andrew Paterson

Senior Associate ScientistsDr. Elise Héon Dr. Peter RayDr. Rosanna Weksberg

Senior Scientist EmeritusDr. Manuel Buchwald


infection, immunity, injury & repair research

HIV INFECTIONPROBIOTICS

PROBIOTICS Chronic stress is implicated in the development of irritable bowel syndrome and in the worsening of symptoms of infl ammatory bowel disease, such as Crohn’s disease and ulcerative colitis. Stress also causes the gut to become sensitized, which can produce food allergies. Dr. Phil Sherman and colleagues at McMaster University have found that probiotics reduce gut symptoms caused by long-term stress. Probiotics are a form of healthy bacteria that are found in some yogurt and other dairy products. Dr. Sherman and colleagues designed their experiments to produce psychological stress in rats similar to that seen in humans. This was done by placing the animals on small platforms surrounded by water. Half the rats were fed drinking water containing probiotic bacteria in the form of Lactobacillus helveticus and Lactobacillus rhamnosus for a period of 10 days before and during the stress sessions. The stress tests were designed to mimic psychological stress to produce the type of effects seen in the human gut.

The investigation showed that exposure to stress made the animals’ guts ‘leaky’ and increased the amount of potentially harmful bacteria adhering to cells lining the gut wall. Harmful bacteria were also detected in the mesenteric lymph nodes, which drain fl uid coming from the intestine, indicating that bacteria had entered the body. The researchers showed that probiotic treatment minimized the changes in chemical signalling and prevented bacterial attachment and movement to the mesenteric lymph nodes. The thinking behind this study is that probiotics compete for space in the gut with harmful bacteria, which helps to minimize infl ammatory responses. This discovery may be a promising method for managing intestinal problems caused by stress, but is still in the preliminary phases of discovery at the animal model level.

NOVEL INHIBITOR OF HIV INFECTION Acquired immunodefi ciency syndrome (AIDS) is a group of symptoms and opportunistic infections resulting primarily from damage to the immune system caused by infection with the human immunodefi ciency virus (HIV). Present treatments for the disease are focused on the use of antiretroviral therapy, which can postpone the later stages of AIDS when the individual falls victim to infections and tumours. Researchers are also focused on vaccine development and preventing transmission of the disease from person to person and cell to cell.

Dr. Clifford Lingwood and colleagues at Canadian Blood Services (CBS) showed that a novel molecule might prevent all types of HIV from infecting different kinds of cells. Dr. Lingwood and his research team described a novel soluble molecule, based on a membrane glycolipid from normal cells, that can prevent many different types of HIV from infecting cells. They had previously shown that this modifi ed glycolipid, called adamantylGb

3, designed by Dr. Murugespillai Mylvaganum in the Lingwood lab, binds to the HIV protein

responsible for binding the virus to cells. They now have found adamantylGb3 to inhibit the infection of cells in vitro by all strains of

HIV. This also correlates with the Lingwood/CBS research team fi nding that cells from people in which the normal Gb3 accumulates

due to a metabolic defect are resistant to HIV. Thus Gb3 (or its soluble derivative, adamantylGb

3) provides a new HIV resistance factor.

AdamantylGb3 works by binding to the virus and preventing the fusion of the virus with the host cell. This is a different mechanism

from most anti-HIV treatments. Even drug-resistant HIV strains remain susceptible to adamantylGb3, which could therefore be of

clinical benefi t when other drugs have failed. AdamantylGb3 may provide the basis of a new treatment or the prevention of transmission

of HIV and/or AIDS. One of the more effective potential applications for the soluble molecule in the prevention of HIV is its utility in a topical microbicide, a gel that can be applied before intercourse to prevent transmission of the virus. To this end, one of the next tasks for the research team is the development of a topical format to prevent sexual transmission of the virus. Additional next steps for the research team include determining the best concentrations and formulations of the molecule in animal models. Mechanisms to increase cellular Gb

3 are also being studied as a means to create HIV resistance.

action & reaction

SCIENTIFIC STAFF

Head & Senior ScientistDr. Chaim Roifman

Senior ScientistsDr. Amos CohenDr. Hans-Michael DoschDr. Clifford LingwoodDr. Philip Sherman

Senior Associate ScientistsDr. Antoine KhouryDr. Stanley Read

ScientistsDr. John BrumellDr. Lori BurrowsDr. John ChamberlainDr. Yigal Dror Dr. Nicola JonesDr. Mary Ann OpavskyDr. Lisa RobinsonDr. Chetankumar Tailor

Scientist-Track InvestigatorDr. Eyal Grunebaum

Associate ScientistsDr. Darius BägliDr. Susan RichardsonDr. Dat TranDr. Peter Kim

Senior Scientists EmeritusDr. Mel Freedman Dr. Patricia Quinn Dr. Robert Salter

HEAD INJURY AND HYPOTHERMIA THERAPY Head injury is the most common cause of death and new disability for people between the ages of one and 24 years worldwide. With a traumatic head injury, irreparable damage and cell death occurs at the moment of impact. Damage to the brain continues after this incident, as cells in and around the injured area swell or become abnormal in appearance and function. Most of these swollen and abnormal cells eventually die and unlike other cell types in the body, brain cells do not regenerate. This kind of cell death is devastating to a patient of any age, but for children in particular the results can be tragic as a child’s brain is still developing.

Dr. Jamie Hutchison wants to understand what the mechanisms are behind brain injury, what factors play into the abnormal appearance and function of the cells and their subsequent death. He is also studying whether lowering the body’s temperature using hypothermia therapy improves mechanisms associated with cell death in the brain. While the primary damage caused by a traumatic brain injury cannot be avoided, the secondary cell swelling and death can be mitigated and avoided by inducing a state of hypothermia in the injured patient. It has been previously shown that individuals who had their body temperature lowered had better results on various cognitive function, intelligence, memory and attention tests administered at various points after recovering from the primary accident. Dr. Hutchison recently completed the world’s largest study on the safety of using hypothermia therapy to treat children with severe traumatic brain injury. The study showed that bringing the body temperature of a child down from 37 C to between 32 C and 33 C was safe and could help control brain swelling.

LEARNING AND MEMORY Drs. Paul Frankland and Sheena Josselyn have been using brain mapping, mouse-genetic, and pharmacological approaches to understand how new memories in the hippocampus are transformed into lifelong, or remote, memories in cortical networks. In particular, their studies show that recall of remote memories activates multiple cortical brain regions, suggesting that these memories are supported by a broad, distributed network of cortical regions.

The expression of immediate early genes correlated with levels of neuronal activity can be used to track changes in the organization of memories at different times after learning. In one of these studies, Drs. Frankland and Josselyn trained mice in a fear conditioning task and tested them either one day or one month later. Patterns of brain activation were dramatically different at the two time points. The hippocampus was strongly activated only following recall of the recent (day-old) fear memory. In contrast, a number of different cortical regions were strongly activated only following recall of the remote (month-old) fear memory. It wasn’t that gene expression was simply driven by fear — the mice showed similar levels of fear in the recent and remote memory tests. Rather, these results suggest that, within the space of a month, the circuits supporting fear memory undergo major reorganization. Together with other imaging studies in mice, they suggest that remote memories are ultimately supported by a broad network of cortical regions.

The team then trained mice with reduced levels of the synaptic protein alpha-CaMKII in the fear-conditioning task. These mice had normal fear memory when tested one day later. However, when tested one month later, their fear memory was completely wiped out. Importantly, cortical activation associated with recall of remote fear memories was also entirely absent in these mice. The absence of cortical activation in these forgetful mice suggests that activity in brain regions such as the ACC (anterior cingulate cortex) plays a crucial role in remote memory recall.

Together, these studies are beginning to identify the network of cortical regions that support remote memory.

LEARNING AND MEMORYHEAD INJURIES

integrative biology


function & image

SCIENTIFIC STAFF

Head & Senior ScientistDr. Martin Post

Senior ScientistsDr. Douglas CheyneDr. Peter DurieDr. Mark HenkelmanDr. Shinya ItoDr. Cho PangDr. Paul Pencharz

ScientistsDr. Josette ChenDr. Paul FranklandDr. Jamie HutchisonDr. Sheena JosselynDr. Christopher MacgowanDr. Colin McKerlieDr. John Sled

Scientist-Track InvestigatorsDr. Hai-Ling (Margaret) ChengDr. Andrea Doria

Senior Associate ScientistsDr. Martin CharronDr. Deborah O’ConnorDr. Margaret Rand

Associate ScientistsDr. Peter CoxDr. Mark Crawford

Senior Scientists EmeritusDr. Susan GoldbergDr. Cecil Pace-Asciak


NITRIC OXIDE THERAPY Nitric oxide (NO) is an important signalling molecule in the body and one of the few known gaseous signalling molecules. Discovered more than 15 years ago, nitric oxide is a messenger molecule that is involved in a variety of biological and physiological processes in the body.

Children with cystic fi brosis (CF) encounter problems because the mucus in their lungs stops serving as a lubricant and instead becomes thick and sticky and clogs the respiratory system. This allows bacteria to grow within it, making children with CF vulnerable to bacterial infections that don’t affect the general public. Immune system cells, bronchial cells and macrophages (any of the large phagocytic cells found in the reticuloendothelial system) produce nitric oxide in order to kill invading bacteria. However, nitric oxide formation is defi cient in the airways of patients with CF. Since nitric oxide is also a bronchodilator, its absence may contribute to airway obstruction in CF patients.

Drs. Felix Ratjen and Hartmut Grasemann are studying the effects of increasing the production of nitric oxide in CF patients. Preliminary data have shown that inhalation of an amino acid that is part of the normal diet and used by the body to produce nitric oxide improves lung function in CF patients. To better understand the balance of nitric oxide formation in the lungs, Drs. Ratjen and Grasemann are using a mouse model with cystic fi brosis. This will help to clarify how nitric oxide defi ciency can best be treated. This information will then be used in future clinical studies in CF patients.

THE INNATE IMMUNE SYSTEM Our immune system protects us from microbes and other harmful materials. Some of these barriers are innate, meaning they are present from birth and are the fi rst defence in an immune response. If something gets past these barriers, it is attacked and destroyed by other sophisticated parts of the innate and adaptive immune systems.

The lungs are essential for breathing. Each day, we inhale several million microorganisms and other particles such as pollen and allergens. Pollen grains and many microbes, including bacteria, fungi and viruses, contain protective coats of sugars, or arrays of carbohydrate molecules, on their surfaces. All of these microbes and particles have to be removed from the airways to maintain healthy lungs for effective breathing.

Dr. Nades Palaniyar works with proteins called surfactant proteins A and D (SP-A and SP-D), which are innate immune proteins. The inner surface of the lungs is lined with airway surface fl uid and 90 per cent of the proteins found in this surfactant fl uid are SP-A and SP-D. These proteins are pattern-recognition molecules and recognize pathogens that have a different sugar signature pattern than that of our own body, and seek them out. Once the invaders are tagged by SP-A and SP-D, immune cells will engulf and destroy them. Therefore, there is no need for our immune system to develop antibodies to all of the microbes as most of them are eliminated by SP-A and SP-D-mediated mechanisms. Innate immune proteins such as SP-A and SP-D are especially important for infants because they do not have antibodies against many pathogens. While adults rely on both innate and adaptive immune systems to defend themselves against microbial infections, neonates and children depend primarily on innate immune system for their protection.

Dr. Palaniyar and his team are working to determine the therapeutic potential of these proteins for the treatment of infl ammatory lung diseases like cystic fi brosis, allergies and asthma.

INNATE IMMUNE SYSTEMNITRIC OXIDE THERAPY

lung biology

inhale & exhale

SCIENTIFIC STAFF

Head & Senior ScientistDr. Martin Post

Senior ScientistsDr. Allan CoatesDr. Jim HuDr. Hugh O’BrodovichDr. Felix RatjenDr. Neil SweezeyDr. Keith Tanswell

ScientistsDr. Brian KavanaghDr. Nades Palaniyar

Scientist-Track InvestigatorDr. Padmaja Subbarao

Senior Associate ScientistsDr. Jaques BélikDr. Ernest Cutz

Associate ScientistDr. Hartmut Grasemann

Senior Scientist EmeritusDr. Charles Bryan


ENERGY PRODUCTION When your body begins to exercise, the fi rst line of energy is adenosine triphosphate (ATP), which provides chemical energy for muscle contraction. For any form of prolonged exercise, the supply of ATP has to be renewed by the oxidation of sugars and fats by mitochondria (the power plants in cells). After a short burst of aerobic exercise, the body starts to process glucose into pyruvic acid, the primary fuel of mitochondria. Entry into the ATP-producing system of mitochondria is through the pyruvate dehydrogenase (PDH) complex. But what if you are born with a gene that alters the regulation of this intake system so that only a small amount gets in and your supply of energy for exercise is severely limited?

Dr. Brian Robinson was approached by a family whose two male children suffered from severe exercise intolerance. The boys became tired extremely rapidly and aerobic exercise was impossible. Physicians ruled out cardiac dysfunction and known glycogen breakdown diseases. Dr. Robinson’s team was sent skin cell cultures from the brothers and was asked to look for a cause of limited energy production.

After analyzing the cultures, the research team found that both children showed decreased activity of the pyruvate dehydrogenase complex caused by a defective regulatory protein PDP1. The cause of the problem had been identifi ed and the solution was remarkably simple. The children were placed on a ketogenic diet, which involves reducing the intake of carbohydrates to the point where the body is forced to use fat, while increasing the percentage of their daily fat intake by 50 to 60 per cent. When carbohydrate intake is reduced, the body begins to use fat as fuel and ketones are delivered to muscle and brain. Ketones are substances that are made when the body breaks down fat for energy. The ketogenic diet was initially a treatment for epilepsy that relies on inducing a state of ketosis to alleviate epileptic symptoms. For the boys with the severe exercise intolerance the new diet means they are able to achieve a normal level of activity.

CARNITINE When they body’s main energy source, glucose, runs out, fat is oxidized and broken down into energy. This is partially done by a compound co-factor called carnitine, which helps the body oxidize fat and turn it into energy. The more carnitine you have in your system, the more effi ciently you oxidize fats. During a prolonged period of exercise, carnitine supplies the body with an extra boost of energy. However, if a child or adult cannot produce carnitine, that energy is not readily available. The inability to produce and utilize carnitine is a fatty oxidation disorder. If left undiagnosed and untreated, these disorders can lead to serious complications affecting the liver, heart, eyes and general muscle development.

Dr. Ingrid Tein is looking at what is needed to move carnitine in and out of cells and in and out of the organelles within the cell. She has described a family of carnitine transporters that are responsible for carnitine movement and uptake. This insight has enabled her to postulate a connection between carnitine transporters and Crohn’s disease. Crohn’s disease is a type of infl ammatory bowel disease that can affect the entire gastrointestinal tract from mouth to anus. Children with Crohn’s disease may suffer from delayed development and stunted growth, though the range and severity of symptoms varies from person to person. It is known that the carnitine transporter is polymorphic, meaning it exists in two forms that differ by one amino acid. Dr. Tein found that only people with one form of the carnitine transporter seem to develop Crohn’s disease. This form of the carnitine transporter exposes a patient to Crohn’s because the immune system confuses it for a bacterial pollen with exactly the same protein sequence and attacks the carnitine in the gut.

The next steps for Dr. Tein involve biochemical and molecular characterization of carnitine transporters and their regulation, and characterization of their mutant states. Further understanding of the forms of these transporters will provide researchers with better tools for determining how the immune system confuses carintine and bacteria, and may lead to the development of novel treatment strategies.

CARNITINEENERGY PRODUCTION

metabolism research

diet & exercise

SCIENTIFIC STAFF

Head & Senior ScientistDr. Brian Robinson

Senior ScientistsDr. Don MahuranDr. Eve RobertsDr. Ingrid TeinDr. Stanley Zlotkin

Senior Associate ScientistsDr. John CallahanDr. Raymond Tellier

Senior Scientist EmeritusDr. Gordon Forstner

OBESITY RISKS Obesity is a major risk factor for Type 2 diabetes. It is a complex disease that involves many environmental and genetic factors. Risk for the development of Type 2 diabetes occurs early in life, and is mediated by weight gain, insulin resistance and problems with insulin secretion. Dr. Jill Hamilton has decided to look at these mechanisms by studying two unique populations of children.

The fi rst study examines the effects of exposure to differing levels of blood glucose (sugar) while in utero in infants of mothers with gestational diabetes. This group of children is known to have an increased long-term risk of developing obesity and Type 2 diabetes. Dr. Hamilton aims to determine the link between maternal factors during pregnancy with early life growth and development in the offspring, as well as early risk for diabetes. This study will allow Dr. Hamilton to assess early risk for obesity and diabetes, and determine how diabetes in pregnancy infl uences outcomes in children. This could lead to early intervention studies to prevent obesity and diabetes in at-risk children.

The other study is investigating children who have had injury to parts of the brain controlling appetite and weight regulation. Injuries to the hypothalamus put children at increased risk for rapid development of obesity and its complications. For example, craniopharyngioma is a benign tumour involving the pituitary and hypothalamus that is treated surgically. Approximately 40 to 60 per cent of children develop obesity after surgery. An important contributing factor for this weight gain may be increased insulin secretion caused by hypothalamic-mediated nerve stimulation of the pancreas.

In a pilot study, Dr. Hamilton plans to treat a small number of youth with hypothalamic obesity following surgery with two oral medications: diazoxide, which acts to lower insulin secretion, and metformin, which improves insulin action and lowers blood sugar levels from the liver. This novel combined therapy may improve insulin secretion and action, thus resulting in weight loss. This therapy may have important implications for others who have increased weight due to excessive secretion of insulin.

SCHIZOPHRENIA IN YOUNG PEOPLE Studies have shown that at least two per cent of the adolescent population in Canada suffers from psychosis, often a precursor to schizophrenia. Schizophrenia is a severe psychiatric disorder that affects an estimated one in 100 Canadians and their families. Detection and intervention early in the development of the disease has been found to be one of the markers of a good prognosis.

Dr. Katherine Boydell is focusing her research on young people who are at high risk of developing psychosis or who have already developed a fi rst episode of psychosis. Dr. Boydell’s research program explores the pathway to mental health care for young people and their families. These studies are important because they will lead to an improved understanding of who seeks help, how they seek help, and the many ways help-seeking is either facilitated or hindered at individual, familial, community and systemic levels of mental health care.

Another neglected area of investigation is the challenge of immigrant youth experiencing a fi rst episode of psychosis. The pattern of social support among ethnic and racial groups varies, and little is known about the meaning of psychosis and the pathways to care among immigrant populations. It is known that immigrant populations are less likely to utilize professional mental health services and delay visits to services until the condition progresses to advanced stages.

Children and families in rural and remote communities also face more obstacles to obtaining mental health services and support than those from urban areas. The problems are multifactorial, resulting from geographic, economic and cultural factors. Dr. Boydell and her group have made great strides in facilitating pathways to mental health by using telepsychiatry as a knowledge translation tool for enhancing capacity for mental health-care providers in rural and remote areas.

SCHIZOPHRENIAOBESITY R ISKS

population health sciences


healthy & active

SCIENTIFIC STAFF

Head & Senior ScientistDr. Teresa To

Senior ScientistsDr. Mary CoreyDr. Brian FeldmanDr. Gideon KorenDr. Brian McCrindleDr. Bonnie StevensDr. Wendy Ungar

Dr. Andrew WillanDr. James Wright

ScientistsDr. Joseph BeyeneDr. Katherine BoydellDr. Gabrielle deVeber Dr. Andrew HowardDr. Lorelei LingardDr. Gail McVeyDr. Anna Taddio

Scientist-Track InvestigatorsDr. Abhaya KulkarniDr. Unni NarayananDr. Christopher ParshuramDr. Robyn StremlerDr. Lillian SungDr. Paul Wales

Senior Associate ScientistsDr. Upton Allen

Dr. Maru BarreraDr. Victor BlanchetteDr. Eric BouffetDr. Joe ClarkeDr. Denis DanemanDr. Debra KatzmanDr. David KennyDr. Alberto PappoDr. Debra PeplerDr. Suzanne Schuh

Associate ScientistsDr. Beverley AntleDr. Melanie BarwickDr. Diane BenoitDr. Kathy BoutisDr. Manuel CarcaoDr. Sharon DellDr. Ran GoldmanDr. Isabela GranicDr. Jill HamiltonDr. Susan King

Dr. Anne MatlowDr. Paul NathanDr. David NicholasDr. Irena NulmanDr. Patricia ParkinDr. Randi Zlotnik Shaul

Senior Scientists EmeritusDr. Max Perlman Dr. Ingeborg Radde


MECHANISMS FOR MYELIN DEGRADATION IN MULTIPLE SCLEROSIS Myelin basic protein (MBP) is an abundant protein in the brain and the second most abundant protein in myelin. Myelin is the multilayered membranous sheath that surrounds and preserves nerve axons and increases the rate of nerve conduction. The myelin sheath is destroyed in multiple sclerosis (MS), resulting in impaired nerve conduction and degeneration. The laboratories of Drs. Mario Moscarello and Joan Boggs found that a modifi cation of MBP, which is increased in patients with MS, makes myelin unstable and susceptible to immune system attacks. MBP comprises about seven per cent of myelin in the brain. Deletion of this protein almost completely prevents myelin formation in the brain and causes much more severe pathology than deletion of any other structural myelin protein.

Multiple forms of MBP exist, differing in charge and size, due to cellular modifi cation of the protein. Drs. Moscarello and Denise Wood discovered that one of the forms was due to the modifi cation of a positively charged amino acid, arginine, to a non-charged amino acid, citrulline. Six arginines were converted to citrulline by peptidyl-arginine deiminase, which is found in normal brains. The amount of citrullinated protein was greatest in childhood and infancy and decreased with development, suggesting it was important for myelin formation. However, it was found to be more abundant in adults with MS. Lowering of the net positive charge of MBP due to citrullination might be involved in the pathogenesis of MS. Drs. Boggs and Moscarello have shown that the change in the form of this protein affects its function.

Dr. Boggs, together with Dr. George Harauz at the University of Guelph, examined the structural changes of MBP when the number of positively charged residues was reduced, as in MS patients. The results suggest a mechanism by which the body’s immune system gains access to myelin antigens, and provides structural insight into a possible pathological mechanism for MS.

ANTIMICROBIALS Antimicrobial peptides are small synthetic proteins that are highly destructive when they are inserted into the membranes of bacteria. The antimicrobials have a positive charge and adhere to bacterial membranes, which are negatively charged. The peptides sink into the bacterial membrane surface and physically rupture the cell, which ultimately destroys it. Bacteria have little recourse against them.

Dr. Charles Deber and his colleagues have developed a novel group of antimicrobial peptides. By studying the detailed mechanisms of how these antimicrobial peptides work and through optimization of their molecular structures down to the smallest amino acid, Dr. Deber’s group can generate a blueprint for targeting bacteria to help stave off infections. In investigating this, the researchers have to ponder why the antimicrobials select the bacteria and not human cells. This selective attacking pattern is the primary reason why antimicrobials are so effective. They target only the bacterial cells invading the body and leave the healthy human cells alone.

Dr. Deber has shown that human cells, such as red blood cells, carry a neutral charge and therefore do not attract the new antimicrobials and thus do not pull them into their membranes. He has also found that cholesterol — which is present in red cell membranes but not in bacterial membranes — acts as a further protectant for human cells as it creates a barrier against the antimicrobials. These new antimicrobials work against many strains of E. coli, against Pseudomonas aeruginosa, which is one of the main pathogens involved in cystic fi brosis, and against Candida albicans, an organism that causes yeast infections. The potential applications of these antimicrobials may be the development of an inhalant for combating CF pathogens, and a topical ointment against yeast infections.

ANTIMICROBIALSMULTIPLE SCLEROSIS

structural biology & biochemistry

molecules & proteins

SCIENTIFIC STAFF

Head & Senior ScientistDr. Lynne Howell

Senior ScientistsDr. Christine BearDr. Joan BoggsDr. Charles DeberDr. Julie Forman-KayDr. Shoshana Wodak

ScientistsDr. John ParkinsonDr. Régis PomèsDr. John RubinsteinDr. Simon Sharpe

Senior Associate ScientistDr. Khosrow Adeli

Senior Scientists EmeritusDr. Janet ForstnerDr. Mario MoscarelloDr. Bibudhendra SarkarDr. Harry SchachterDr. G. David Smith

Where there is research there is research training. While The Hospital for Sick Children Research Institute offers the necessary scientifi c components to become a successful scientist, there are several other factors necessary for success. Trainees include summer students, graduate students, research fellows and clinician-scientists conducting research at the hospital. To ensure that the more than 900 trainees at the SickKids Research Institute pursuing research careers receive the highest possible quality of training, encompassing all components of research performed at SickKids, the Research Institute provides a variety of trainee-centred programs.

The Research Training Centre (RTC) was established in 1996 in response to a need for a more coordinated and integrated approach for research nurses, health professionals, clinicians and bench scientists training at SickKids. In this regard, the RTC has created an excellent resource and support centre for students, fellows and faculty. The RTC enables and enhances both research and clinical care through the provision of training to create independent researchers and the provision of training to create individuals with discerning familiarity to research activity and the potential to be collaborators.

Through this commitment to student success, the RTC also offers a number of funding opportunities to trainees from varied health and research backgrounds. These funding competitions are reviewed by the scientifi c staff at SickKids and offer much-needed feedback and opportunities for development within the academic environment. The RTC also offers its own seminar series that includes grant writing and preparation, manuscript preparation and how to give a great seminar, as well as invited research talks.

THE FUTURE OF RESEARCHINVESTMENT

research training


Through programs like the Clinician-Scientist Training Program – where clinicians gain the tools necessary to function in the future as independent scientists in the fi eld of child health, or the Samuel Lunenfeld Research Summer Student Program – where undergraduate students are given the opportunity to work and study in a SickKids research lab, trainees at SickKids have an unparalleled opportunity for professional growth as part of a supportive and intellectually challenging institution.

The SickKids training environment welcomes not only Canadian researchers, but also hundreds of trainees from around to the world. With almost 50 per cent of trainees at SickKids coming from outside of Canada, the Research Institute provides students with a world-class education they can use as they join the Canadian research community or take with them back to their country of origin.

This model for research training within a teaching hospital has become a proven success, with research hospitals across the Toronto and Canada adopting the RTC model to provide their trainees with the best experience and climate for scientifi c discovery and achievement.

today & tomorrow

“ The environment of research excellence at SickKids attracts trainees from across Canada and around the world. I’m so proud of the role SickKids and its Research Training Centre plays in preparing the next generation of health researchers.” Dr. Amira Klip, DIRECTOR, RESEARCH TRAINING CENTRE

Bagshaw RD, Callahan JW, Mahuran DJ. The Arf-family protein, Arl8b, is involved in the spatial distribution of lysosomes. Biochemical and biophysical research communications 2006;344(4):1186-91.

Barnabe-Heider F, Wasylnka JA, Fernandes KJL, Porsche C, Sendtner M, Kaplan DR, Miller FD. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 2005;48(2):253-65.

Boright AP, Paterson AD, Mirea L, Bull SB, Mowjoodi A, Scherer SW, Zinman B, Group DER. Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes 2005;54(4):1238-44.

Cameron JM, Hurd T, Robinson BH. Computational identifi cation of human mitochondrial proteins based on homology to yeast mitochondrially targeted proteins. Bioinformatics 2005;21(9):1825-30.

Cantin AM, Hanrahan JW, Bilodeau G, Ellis L, Dupuis A, Liao J, Zielenski J, Durie P. Cystic fi brosis transmembrane conductance regulator function is suppressed in cigarette smokers. American Journal of Respiratory & Critical Care Medicine 2006;173(10):1139-44.

Ching RW, Dellaire G, Eskiw CH, Bazett-Jones DP. PML bodies: a meeting place for genomic loci? Journal of Cell Science 2005;118(Pt 5):847-54.

Costantini DL, Arruda EP, Agarwal P, Kim K-H, Zhu Y, Zhu W, Lebel M, Cheng CW, Park CY, Pierce SA, Guerchicoff A, Pollevick GD, Chan TY, Kabir MG, Cheng SH, Husain M, Antzelevitch C, Srivastava D, Gross GJ, Hui C-c, Backx PH, Bruneau BG. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Cell 2005;123(2):347-58.

Coull JAM, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005;438(7070):1017-21.

Das B, Yeger H, Tsuchida R, Torkin R, Gee MFW, Thorner PS, Shibuya M, Malkin D, Baruchel S. A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated

protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Research 2005;65(16):7267-75.

Dennis M, Edelstein K, Hetherington R, Copeland K, Frederick J, Blaser SE, Kramer LA, Drake JM, Brandt M, Fletcher JM. Neurobiology of perceptual and motor timing in children with spina bifi da in relation to cerebellar volume. Brain 2004;127(Pt 6):1292-301.

Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR, Gene Modifi er Study G. Genetic modifi ers of lung disease in cystic fi brosis. New England Journal of Medicine 2005;353(14):1443-53.

Feuk L, MacDonald JR, Tang T, Carson AR, Li M, Rao G, Khaja R, Scherer SW. Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genetics 2005;1(4):e56.

Frankland PW, Bontempi B. The organization of recent and remote memories. Nature Reviews Neuroscience 2005;6(2):119-30.

Glukhov E, Stark M, Burrows LL, Deber CM. Basis for selectivity of cationic antimicrobial peptides for bacterial versus mammalian membranes. Journal of Biological Chemistry 2005;280(40):33960-7.

Grasemann H, Schwiertz R, Matthiesen S, Racke K, Ratjen F. Increased arginase activity in cystic fi brosis airways. American Journal of Respiratory & Critical Care Medicine 2005;172(12):1523-8.

Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo LD, Roifman CM. Bone marrow transplantation for severe combined immune defi ciency. JAMA 2006;295(5):508-18.

Guttmann A, Manuel D, Dick PT, To T, Lam K, Stukel TA. Volume matters: physician practice characteristics and immunization coverage among young children insured through a universal health plan. Pediatrics 2006;117(3):595-602.

Hansen KK, Sherman PM, Cellars L, Andrade-Gordon P, Pan Z, Baruch A, Wallace JL, Hollenberg MD, Vergnolle N. A major role for

proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proceedings of the National Academy of Sciences of the United States of America 2005;102(23):8363-8.

Heon E, Westall C, Carmi R, Elbedour K, Panton C, Mackeen L, Stone EM, Sheffi eld VC. Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome. American Journal of Medical Genetics Part A 2005;132(3):283-7.

Huang A, Ho CSW, Ponzielli R, Barsyte-Lovejoy D, Bouffet E, Picard D, Hawkins CE, Penn LZ. Identifi cation of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Research 2005;65(13):5607-19.

Ishiki M, Randhawa VK, Poon V, Jebailey L, Klip A. Insulin regulates the membrane arrival, fusion, and C-terminal unmasking of glucose transporter-4 via distinct phosphoinositides. Journal of Biological Chemistry 2005;280(31):28792-802.

Jacobs WB, Govoni G, Ho D, Atwal JK, Barnabe-Heider F, Keyes WM, Mills AA, Miller FD, Kaplan DR. p63 is an essential proapoptotic protein during neural development. Neuron 2005;48(5):743-56.

Kalnins D, Corey M, Ellis L, Durie PR, Pencharz PB. Combining unprotected pancreatic enzymes with pH-sensitive enteric-coated microspheres does not improve nutrient digestion in patients with cystic fi brosis. Journal of Pediatrics 2005;146(4):489-93.

Khambalia A, MacArthur C, Parkin PC. Peer and adult companion helmet use is associated with bicycle helmet use by children. Pediatrics 2005;116(4):939-42.

Koehler DR, Martin B, Corey M, Palmer D, Ng P, Tanswell AK, Hu J. Readministration of helper-dependent adenovirus to mouse lung. Gene Therapy 2006;13(9):773-80.

Kornecki A, Tsuchida S, Ondiveeran HK, Engelberts D, Frndova H, Tanswell AK, Post M, McKerlie C, Belik J, Fox-Robichaud A, Kavanagh BP. Lung development and susceptibility to ventilator-induced lung injury. American Journal of Respiratory & Critical Care Medicine 2005;171(7):743-52.

LEADING THE WAYINSIGHT

high-impact papers


Koshiba-Takeuchi K, Takeuchi JK, Arruda EP, Kathiriya IS, Mo R, Hui C-c, Srivastava D, Bruneau BG. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature Genetics 2006;38(2):175-83.

Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN, Nielsen TT, Botker HE. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism. American Journal of Physiology - Heart & Circulatory Physiology 2005;288(3):H1252-6.

Krogan NJ, Cagney G, Yu H, Zhong G, Guo X, Ignatchenko A, Li J, Pu S, Datta N, Tikuisis AP, Punna T, Peregrin-Alvarez JM, Shales M, Zhang X, Davey M, Robinson MD, Paccanaro A, Bray JE, Sheung A, Beattie B, Richards DP, Canadien V, Lalev A, Mena F, Wong P, Starostine A, Canete MM, Vlasblom J, Wu S, Orsi C, Collins SR, Chandran S, Haw R, Rilstone JJ, Gandi K, Thompson NJ, Musso G, St Onge P, Ghanny S, Lam MHY, Butland G, Altaf-Ul AM, Kanaya S, Shilatifard A, O’Shea E, Weissman JS, Ingles CJ, Hughes TR, Parkinson J, Gerstein M, Wodak SJ, Emili A, Greenblatt JF. Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Nature 2006;440(7084):637-43.

Kus B, Gajadhar A, Stanger K, Cho R, Sun W, Rouleau N, Lee T, Chan D, Wolting C, Edwards A, Bosse R, Rotin D. A high throughput screen to identify substrates for the ubiquitin ligase Rsp5. Journal of Biological Chemistry 2005;280(33):29470-8.

Lamhonwah AM, Tein I. Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian mitochondria. Biochemical and biophysical research communications 2006;345(4):1315-25.

Lee JE, Singh V, Evans GB, Tyler PC, Furneaux RH, Cornell KA, Riscoe MK, Schramm VL, Howell PL. Structural rationale for the affi nity of pico- and femtomolar transition state analogues of Escherichia coli 5’-methylthioadenosine/S-adenosylhomocysteine nucleosidase. Journal of Biological Chemistry 2005;280(18):18274-82.

Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN. Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis. Journal of Molecular Biology 2006;359(4):913-29.

Leung-Hagesteijn C, Hu MC, Mahendra AS, Hartwig S, Klamut HJ, Rosenblum ND, Hannigan GE. Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis. Molecular & Cellular Biology 2005;25(9):3648-57.

Lohi H, Ianzano L, Zhao X-C, Chan EM, Turnbull J, Scherer SW, Ackerley CA, Minassian BA. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Human Molecular Genetics 2005;14(18):2727-36.

Maj MC, MacKay N, Levandovskiy V, Addis J, Baumgartner ER, Baumgartner MR, Robinson BH, Cameron JM. Pyruvate dehydrogenase phosphatase defi ciency: identifi cation of the fi rst mutation in two brothers and restoration of activity by protein complementation. Journal of Clinical Endocrinology & Metabolism 2005;90(7):4101-7.

Mill P, Mo R, Hu MC, Dagnino L, Rosenblum ND, Hui C-C. Shh controls epithelial proliferation via independent pathways that converge on N-Myc. Developmental Cell 2005;9(2):293-303.

Musse AA, Boggs JM, Harauz G. Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope.[see comment]. Proceedings of the National Academy of Sciences of the United States of America 2006;103(12):4422-7.

Padela S, Cabacungan J, Shek S, Belcastro R, Yi M, Jankov RP, Tanswell AK. Hepatocyte growth factor is required for alveologenesis in the neonatal rat. American Journal of Respiratory & Critical Care Medicine 2005;172(7):907-14.

Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR, Lockwood G, Egan SE. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Research 2005;65(18):8530-7.

Ridsdale R, Roth-Kleiner M, D’Ovidio F, Unger S, Yi M, Keshavjee S, Tanswell AK, Post M. Surfactant palmitoylmyristoylphosphatidylcholine is a marker for alveolar size during disease. American Journal of Respiratory & Critical Care Medicine 2005;172(2):225-32.

Roifman CM, Gu Y, Cohen A. Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome. Journal of Allergy & Clinical Immunology 2006;117(4):897-903.

Schachar RJ, Crosbie J, Barr CL, Ornstein TJ, Kennedy J, Malone M, Roberts W, Ickowicz A, Tannock R, Chen S, Pathare T. Inhibition of motor responses in siblings concordant and discordant for attention defi cit hyperactivity disorder. American Journal of Psychiatry 2005;162(6):1076-82.

Scolnik D, Coates AL, Stephens D, Da Silva Z, Lavine E, Schuh S. Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial. JAMA 2006;295(11):1274-80.

Semotok JL, Cooperstock RL, Pinder BD, Vari HK, Lipshitz HD, Smibert CA. Smaug recruits the CCR4/POP2/NOT deadenylase complex to trigger maternal transcript localization in the early Drosophila embryo. Current Biology 2005;15(4):284-94.

Snead OC, 3rd, Gibson KM. Gamma-hydroxybutyric acid. New England Journal of Medicine 2005;352(26):2721-32.

Taddio A, Lee C, Yip A, Parvez B, McNamara PJ, Shah V. Intravenous morphine and topical tetracaine for treatment of pain in preterm neonates undergoing central line placement. JAMA 2006;295(7):793-800.

Taddio A, Soin HK, Schuh S, Koren G, Scolnik D. Liposomal lidocaine to improve procedural success rates and reduce procedural pain among children: a randomized controlled trial. CMAJ Canadian Medical Association Journal 2005;172(13):1691-5.

Tan JB, Visan I, Yuan JS, Guidos CJ. Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nature Immunology 2005;6(7):671-9.

Tollinger M, Kay LE, Forman-Kay JD. Measuring pK(a) values in protein folding transition state ensembles by NMR spectroscopy. Journal of the American Chemical Society 2005;127(25):8904-5.

Touret N, Paroutis P, Terebiznik M, Harrison RE, Trombetta S, Pypaert M, Chow A, Jiang A, Shaw J, Yip C, Moore H-P, van der Wel N, Houben D, Peters PJ, de Chastellier C, Mellman I, Grinstein S. Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell 2005;123(1):157-70.

Wong R, Hadjiyanni I, Wei H-C, Polevoy G, McBride R, Sem K-P, Brill JA. PIP2 hydrolysis and calcium release are required for cytokinesis in Drosophila spermatocytes. Current Biology 2005;15(15):1401-6.

Yan M, Collins RF, Grinstein S, Trimble WS. Coronin-1 function is required for phagosome formation. Molecular Biology of the Cell 2005;16(7):3077-87.

Yang K, Puel A, Zhang S, Eidenschenk C, Ku C-L, Casrouge A, Picard C, von Bernuth H, Senechal B, Plancoulaine S, Al-Hajjar S, Al-Ghonaium A, Marodi L, Davidson D, Speert D, Roifman C, Garty B-Z, Ozinsky A, Barrat FJ, Coffman RL, Miller RL, Li X, Lebon P, Rodriguez-Gallego C, Chapel H, Geissmann F, Jouanguy E, Casanova J-L. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 2005;23(5):465-78.


technology & knowledge transferBUSINESS & PARTNERSHIPS COMMUNIT Y

As Canada’s most research-intensive hospital and the country’s largest paediatric academic health sciences centre, SickKids continues to be at the forefront of Canada’s health research discoveries. While the primary focus of the SickKids Research Institute is teaching and research, often the products of scholarship have application as new knowledge, products and services beyond the gates of academia.

The primary focus of the Business & Partnership Development team at SickKids is to facilitate the transfer of SickKids’ developed knowledge and technologies into the marketplace by protecting the invention or work (intellectual property) through patents and copyrights and licensing the protected intellectual property to companies outside of SickKids.

In 2005-2006, the Business & Partnership Development Offi ce (now known as the Corporate Ventures unit) managed 267 research contracts with industrial partners, generating more than $3.5 million in research funds for SickKids. Additionally, $2,598,532 in licensing revenues was received; 20 intellectual property license and option agreements with private sector

partners were executed; 21 invention disclosures (from SickKids scientists) were considered for patent protection; 25 new and ongoing patent applications were fi led; and nine patents and trademarks were issued.

The Business & Partnership Development team offers a full range of services to ensure effective technology and knowledge transfer and contract/policy compliance between SickKids and external entities. These services include:

Disclosure facilitation, patenting and other intellectual property protections> Working with SickKids staff and scientists in identifying and evaluating valuable intellectual property assets.> Devising and executing an effective patent, copyright or trademark strategy.> Handling all agreements and details associated with intellectual property protection.

Technology commercialization> Undertaking scientifi c and market assessments of SickKids’ inventions and technologies.> Actively marketing SickKids’ technologies to potential partners.

> Creating confi dentiality, evaluation, material transfer, option and license agreements with partners, which help to effectively transfer SickKids-derived technology into commercial applications.

Technology advancement> Working with federal and provincial government commercialization initiatives whose aim is to advance early-stage discoveries/inventions towards realizable and commercializable technologies (e.g. Proof-of-Principle initiative funded by the Canadian Institutes of Health Research – CIHR).> Partnering with industry to advance basic and clinical research.

Knowledge transfer > Facilitating the uptake of new knowledge by the external community (e.g. book publishing and teaching programs).

Contract negotiation with external partners> Drafting, reviewing and negotiating of agreements to ensure they accurately describe the responsibilities of the parties and comply with SickKids policies and risk management strategies.

investigate & invest

technology & knowledge transfer success stories

Rett syndrome gene license Rett syndrome is a progressive neurodevelopmental disorder caused by mutations in the MECP2 gene in approximately 80 per cent of affected individuals. The discovery of an alternate form of this disease gene, along with methods for medical diagnosis, was made by Dr. Berge Minassian of SickKids and Dr. John Vincent of the Centre for Addiction and Mental Health (CAMH). Based on this invention, SickKids and CAMH have partnered with leading providers of advanced neurological diagnostics tests to offer this valuable diagnostic tool to physicians in Canada, the United States, Japan and Europe.

Moving research from the laboratory bench to the clinic CIHR’s Proof-of-Principle program supported continued in vitro and in vivo testing of novel therapeutic compounds developed by Dr. Don Mahuran and Dr. Michael Tropak from SickKids, as well as Dr. Stephen Withers at the University of British Columbia, for the treatment of adult-onset Tay-Sachs and Sandhoff diseases. The resultant translational studies convinced a private sector partner to in-license the technology from SickKids and design a clinical development plan for advanced pre-clinical studies with the expressed aim of fi ling an IND (Investigational New Drug) application with the FDA (Food and Drug Adminsitration) for human trials.

Alliances to support research activities Continued private sector sponsored research in the laboratory of Dr. Aleksander Hinek has led to further research aimed at trying to understand the role of manganese/iron salts in the production of increased elastin fi bres and new connective tissue synthesis in skin. Applications of this research have led directly to the development of technology important for improved wound healing and skin repair.

Sharing SickKids expertise through book publishing Staff at the hospital continued to meet professional and public needs for quality children’s health information this year. Written by SickKids health-care professionals, the following books were published under the SickKids logo, providing the most up-to-date, expert-advice, with easy-to-read information: Better Food for Pregnancy, Daina Kalnins and Joanne Sabb (Publisher, Robert, Rose Inc.); Caring for Kids: The Complete Canadian Guide to Children’s Health, Dr. Jeremy Friedman and Dr. Norman Saunders (Publisher, Key Porter Books); Get a Healthy Weight for your Child, Dr. Brian McCrindle and James Wengle (Publisher, Robert Rose Inc.); Help for Eating Disorders, Dr. Deborah Katzman and Dr. Leora Pinhas (Publisher, Robert Rose Inc.); and The Hospital for Sick Children Atlas of Pediatrics, Dr. Ronald Laxer, Editor-in-Chief (Publisher, Current Medicine). The commercial books are available for sale in person in the The 5 Fifty 5 Shop at SickKids, online at www.shopsickkids.com and at most retail outlets.

facilities

CORE FACILITIES

Advanced Bioimaging Centre The Advanced Bioimaging Centre is a joint facility of SickKids and Mount Sinai Hospital. It is located in the Department of Pathology and Laboratory Medicine at Mount Sinai Hospital and provides electron microscopy services to scientists at both institutions, as well as the University of Toronto and the scientifi c community at large.

Advanced Protein Technology Centre The Advanced Protein Technology Centre (APTC) provides protein analysis services to the Canadian research community. APTC services include amino acid analysis, peptide sequencing, peptide synthesis and mass spectrometry.

Centre for Computational Biology The Centre for Computational Biology (CCB) is the computational support and service group for the SickKids Research Institute. From desktop support and application development to computing resources and bioinformatics consulting, the CCB provides a full range of computational support and services, as well as supercomputing services.

Clinical Research Support Unit The mandate of the Clinical Research Support Unit (CRSU) is to improve the quality of clinical research at SickKids by providing consultation in the areas of study design and methodology, statistical analysis, and data management.

Clinical Research Centre The Clinical Research Centre was established to provide safe and accessible facilities for physiological types of patient-based research. Services provided include a cardiopulmonary research exercise laboratory and a clinical investigation unit that offers general patient assessment, specialized metabolic testing and bioelectrical impedance.

Transgenic Facility and Mouse Embryonic Stem Cell Facility The Transgenic Facility is a resource centre containing a collection of laboratory equipment required for procedures involved in mouse embryo research. The Mouse Embryonic Stem (ES) Cell Facility is a core facility that provides services for gene-targeting experiments, including growing ES cells and feeder cells, electroporation of targeting vectors, and selection and expansion of targeted ES cell clones.

Flow Cytometry Facility The Flow Cytometry Facility allows for cell analysis using fl ow cytometry technology. Flow cytometers detect and quantify a number of cellular parameters as cells are carried in a liquid stream through a nozzle that is illuminated by one or more lasers emitting light of defi ned wavelengths.

Imaging Facility Laser confocal microscopy and deconvolution microscopy are considered optimal systems for detection of fl uorescent molecules with high resolution. Multi-photon excitation extends the capabilities of the confocal system by increasing the focal depth and minimizing photodynamic damage to the biological system. The high energy of the tunable laser is also ideal for photo-activation or photo-bleaching experiments. Most of the equipment in the Imaging Facility is not available elsewhere in Toronto, including laser tweezers and scissors that can manipulate individual organelles.

Monoclonal Antibody Facility The Monoclonal Antibody Facility provides services for custom hybridoma production and antibody purifi cation to the Canadian research community.

The Centre for Applied Genomics The Centre for Applied Genomics (TCAG) is comprised of facilities that provide the resources, technologies and expertise essential for disease gene research and other basic and applied genetic and genomic investigations. Along with DNA sequencing and synthesis, TCAG facilities include:> The Genetic Analysis Facility, which includes genome-wide scans, fi ne-mapping genotyping, marker development and mutation analysis.> The Genome Resource Facility provides a gene and physical mapping service.> The Gene Isolation and Expression Facility uses state-of-the-art technologies to facilitate the isolation of candidate genes from defi ned chromosome regions, to facilitate the isolation of full-length genes through library screening, RT-PCR and RACE, and to determine tissue expression profi les of genes of interest.> The Microarray Facility performs both gene expression studies and array-based comparative genomic hybridization.

PROJECT FACILITIES

The Mouse Imaging CentreThe Mouse Imaging Centre (MICe) combines state-of-the-art digital imaging technologies for the characterization of mouse models of human disease and phenotype discovery.

SIDNET SIDNET is a project that aims to express the human proteome and study human function by high throughput screens, thereby allowing the study of cellular proteins. The SIDNET protein archive enables users to access a vast library of protein clone information, as well as search a protein database.


NUMBER OF PRINCIPAL INVESTIGATORS: 235NUMBER OF PROJECT DIRECTORS (Clinicians leading a research project): 202NUMBER OF TRAINEES: 961 Number of research fellows: 315 Number of graduate students: 453 Number of clinician-scientists: 7 Number of summer students 186NUMBER OF GRANT-FUNDED STAFF: 639NUMBER OF OPERATIONS STAFF: 163NUMBER OF ADMINISTRATIVE SUPPORT STAFF: 63NUMBER OF FUNDED PROJECTS: 1,482NUMBER OF ACTIVE CLINICAL PROTOCOLS: 1971TOTAL INFRASTRUCTURE GRANTS: $ 24,310,248TOTAL OPERATING GRANTS: $ 59,870,778TOTAL PERSONNEL AWARDS: $ 8,962,178TOTAL RESEARCH BUDGET: $ 139,729,201

BY THE NUMBERS 2005-2006

quick stats


financials 2005-2006

Type & Number Amount

AWARDS

Senior Investigator (3) $ 170,962 Investigator (9) 419,406 New Investigator (13) 718,309 Canada Research Chair I (16) 2,763,349 Canada Research Chair II (11) 1,051,824 Clinician Scientist (4) 293,024 Fellowship (79) 2,132,751 Graduate Studentship (98) 1,380,800 Summer Studentship (7) 31,753 Total Awards (240) 8,962,178 PROJECTS

Research Project (975) $ 50,580,071 Sponsored Research - Basic (48) 1,251,470 Sponsored Research - Clinical (219) 2,241,628 Infrastructure Grants (48) 24,310,248 Equipment (14) 267,719 Maintenance (5) 800,532 OPERATIONS

SickKids Foundation $ 31,568,711 Commercial Services at SickKids 5,947,103 Indirect Cost Recovery 6,560,822 Billing Recovery 400,00 Investment Income 6,838,719 Total Projects and Operations $ 130,767,023 Total Funding $ 139,729,201

funding by type

funding by sector

funding by source

1. SickKids Foundation (including RI operating grant, restricted donations and endowments) 23% 2. Canadian Institutes of Health Research 18% 3. Genome Canada/Ontario Genomics Institute 6% 4. Commercial Services at SickKids 4% 5. US National Institutes of Health 4% 6. Canada Foundation for Innovation 3% 7. Ontario Innovation Trust 3% 8. Investment Income 3% 9. Canadian Institutes of Health Research Indirect Costs 3% 10. Canada Research Chairs Program 3% 11. National Cancer Institute of Canada 2% 12. Ontario Ministry of Research & Innovation 2% 13. Heart and Stroke Foundation of Ontario 2% 14. Ontario Research Performance Fund 2% 15. Other Research Sponsors (see complete list pp. 39-41) 22% 100%

1. Federal 38% 2. Industry 4% 3. Provincial 10% 4. US 6% 5. Other* 42%

67

8

9

10

11121314

15 1

2

345

4 3

2

5

1

fi nancials

* Other includes disease-specific granting agencies and non-profit foundations


funding by source

3M Pharmaceuticals Canada $ 8,404

Abbott Laboratories Limited 61,605

Actelion Pharmaceuticals Ltd. 53,266

Aegera Therapeutics Inc. 3,943

Agouron Pharmaceuticals, Inc. 24,272

Alberta Heritage Foundation for Medical Research 5,479

Allergen - Allergy, Genes and Environment Network 152,755

Alzheimer Association 63,405

American Academy of Neurology Foundation 53,819

American Heart Association 68,016

Amgen Inc. 62,458

Amyotrophic Lateral Sclerosis Society of Canada 41,574

Anemia Institute for Research and Education 47,518

Applied Biosystems Canada 209,907

Applied Spectral Imaging Inc. 3,451

Aprica Childcare Institute 6,151

APTC-Billings 13,762

Ares-Serono Group 4,168

Array Biopharma Inc 20,057

AstraZeneca Canada Inc. 141,135

AstraZeneca, UK Ltd. 23,902

Aventis Pharma Inc. 13,901

Axcan Pharma Inc. 2,899

B.C. Research Institute for Children’s & Women’s Health Centre 8,750

b.r.a.i.n.CHILD 394,386

Banting and Best Diabetes Centre 37,133

Baxter Healthcare Corporation 7,279

Bayer Healthcare 37,532

Bayer Inc. 254,029

Beckman Instruments Inc/Coulter 50,434

Bio Marin/Genzyme LLC 36,748

Biocomputing Platforms Ltd. 17,190

Biogen Canada 55,812

BioMarin Pharmaceuticals Inc. 57,495

Bloorview Children’s Hospital Foundation 8,494

Boehringer Ingelheim 29,008

Boston Scientific 436,294

Boston University 78,082

Brain Tumor Foundation of Canada 10,661

Burroughs Wellcome Fund 51,554

C17 Network 15,528

Canada Foundation for Innovation 4,842,662

Canada Research Chairs Program $ 3,464,227

Canadian Allergy, Asthma and Immunology Foundation 5,293

Canadian Arthritis Network 123,363

Canadian Association of Gastroenterology 264,246

Canadian Breast Cancer Foundation 97,011

Canadian Cystic Fibrosis Foundation 1,598,478

Canadian Diabetes Association 111,199

Canadian Foundation for AIDS Research 136,376

Canadian Foundation for Dietetic Research 1,924

Canadian Foundation for Women’s Health 18,552

Canadian Genetic Diseases Network 91,118

Canadian Health Services Research Foundation 55,898

Canadian Hemophilia Society 45,292

Canadian HIV Trials Network 35,005

Canadian Institutes of Health Research 25,824,786

Canadian Institutes of Health Research Indirect Costs 3,935,179

Canadian Language and Literacy Research Network 42,347

Canadian Liver Foundation 2,722

Canadian Lung Association 75,740

Canadian Marfan Association 2,000

Canadian Paediatric Society 84,489

Canadian Psychiatric Research Foundation 9,745

Canadian Society of Clinical Chemists 36,475

Canadian Society of Clinical Pharmacology 11,440

Canadian Stroke Network 154,393

Cancer Care Ontario 101,654

Cancer Research Society 110,505

Cangene Corporation 64,292

Carl Zeiss Canada 69,774

Carsen Group Inc. 84,750

Centocor, Inc. 36,658

Child Neurology Foundation 19,605

Children’s Brain Tumor Foundation 18,183

Children’s Hospital of The King’s Daughters 6,296

Children’s Oncology Group 2,186

Cleveland Clinic Foundation 131,614

Commercial Services at SickKids 5,947,103

Cure Autism Now Foundation 6,944

Cystic Fibrosis Foundation (USA) 25,321

Cystic Fibrosis Foundation Therapeutics, Inc. 99,848



funding by source - cont inued

Danone Institute $ 7,878

Dazai Research Instruments 13,179

Diamed Lab Supplies Inc 5,088

Duchesnay Inc. 150,619

E.A. Baker Foundation for the Prevention of Blindness of the CNIB 10,820

Elastin Specialties Ltd. 29,386

Eli Lilly Canada Inc. 140,391

ESBE Scientific 37,244

ethica Clinical Research Inc. 26,131

Fanconi Canada 19,161

Fisher Scientific Ltd. 22,626

Foundation of Digestive Health and Nutrition 107,920

Fujisawa Canada Inc. 76,783

Garrod Association 15,230

GE Medical System 71,463

Genesis Bio-Pharmaceuticals, Inc. 11,351

Genome Canada/ Ontario Genomics Institute 7,762,369

Genzyme Corporation 3,904

GlaxoSmithKline 119,161

Graduate Student Awards Endowment 713,574

Health Canada 423,856

Heart and Stroke Foundation of Canada 168,727

Heart and Stroke Foundation of Ontario 2,281,808

Helios/Oceana (On-the-Go) 24,657

Hoffmann-La Roche Inc. 20,480

Howard Hughes Medical Institute 20,118

Human Frontier Science Program 75,276

Human Matrix Sciences, LLC 8,091

Ian Douglas Bebensee Foundation 42,769

IBM Canada Ltd. 8,108

Illumina Inc 97,453

Indirect Costs, Other Grants 648,062

Industry REB Fees 49,018

Institute Clinical Evaluation Society 185,931

Interface Biologics 20,604

Investment Income 4,521,098

J.P. Bickell Foundation 1,665,159

J.R. Robertson Estate 652,462

Janssen-Ortho Inc. 1,733

Jeffery Modell Foundation 5,608

John Wiley & Sons Inc. 11,806

Juvenile Diabetes Research Foundation International 427,260

Katie’s Kids for the Cure $ 104,573

Lawson Foundation 43,578

Leica Micro Systems Canada Inc 3,196

Leukemia & Lymphoma Society 611,604

LISI Therapeutics, Inc. 9,166

Lymphosign Inc 88,052

Macula Vision Research Foundation 61,289

Mandel Scientific Company Inc 5,004

March of Dimes Birth Defects Foundation 129,567

Marine Biotech 30,455

McDavis Sales & Service Ltd 47,509

McLaughlin Centre for Molecular Medicine 210,392

MDS Proteomics, Inc. 94,145

MedImmune Inc. 18,505

Medrad Inc. 10,796

Merck & Co. Inc. 48,308

Merck Frosst Canada 96,555

Michael Smith Foundation for Health Research 2,508

Miscellaneous 2,759,192

MITACS - Mathematics of Information Technology and Complex Systems 34,156

Molecular Devices Corporation 6,505

Montreal Biotechnologies Inc. 5,766

Mount Sinai Hospital 9,646

Multiple Sclerosis Scientific Research Foundation 685,063

Multiple Sclerosis Society of Canada 350,264

Muscular Dystrophy Association 133,874

National Alliance for Research on Schizophrenia and Depression 48,563

National Cancer Institute of Canada 3,266,422

National Childhood Cancer Foundation 357,118

National Institutes of Health 5,781,277

Natural Sciences and Engineering Research Council of Canada 617,882

Nestec Ltd. 13,814

Neuroscience Canada 883,057

Neurosurgery Research and Education Foundation 23,718

Nikon Canada Inc. 4,869

Noci Pharm Inc. 6,170

North American Pediatric Renal Transplant Case Study 34,263

Novartis Farmaceutica, S. A. 162,215

Novartis Pharmaceuticals Canada Inc. 28,697

Novo Nordisk Canada Inc. 4,548

NOVX Systems 5,748


Ontario Cancer Research Network $ 913,758

Ontario Council of Graduate Studies 47,524

Ontario HIV Treatment Network 99,446

Ontario Innovation Trust 4,624,911

Ontario Lung Association 71,134

Ontario Mental Health Foundation 72,921

Ontario Ministry of Education 370,515

Ontario Ministry of Health and Long-Term Care 578,354

Ontario Ministry of Research & Innovation 2,905,182

Ontario Ministry of Research & Innovation, Early Researcher Award program 114,621

Ontario Neurotrauma Foundation 70,441

Ontario Research Development Challenge Fund 1,418,218

Ontario Research Performance Fund Revenue 1,977,581

Ortho-Clinical Diagnostics Inc. 89,977

OSI Pharmaceuticals 3,340

Ovation Pharmaceuticals, Inc. 69,139

Paediatric Consultants 88,233

PARI GmbH 28,040

Parkinson Society of Canada 19,292

Pediatric Orthopaedic Society of North America 19,959

PENCE Inc. - Protein Engineering Network 104,651

PerkinElmer Canada 21,205

Personnel Awards Recoveries 1,076,732

Pfizer Canada 4,500

Pfizer Inc. 102,130

Pharmacia Canada Inc. 16,244

Philips Medical Systems 197,287

Physicians’ Services Incorporated Foundation 412,422

Premier’s Research Excellence Awards 563,662

Provincial Centre of Excellence for Child and Youth Mental Health 26,669

Psychiatry Endowment Fund 155,030

Quorum Technologies Inc. 40,730

Resverlogix Corporation 28,541

Rethink Breast Cancer 41,813

Rett Syndrome Research Foundation 157,921

Rimon Therapeutics Limited 3,021

Roasters Foundation 1,857

Ross Products Division, Abbott Laboratories 94,084

Royal College of Physicians and Surgeons of Canada 4,242

Sanofi Pasteur Ltd (Aventis Pasteur Ltd) $ 11,507

Savoy Foundation for Epilepsy 23,712

Scalar Decisions 4,808

Schering Canada Inc. 15,461

Scottish Rite Charitable Foundation of Canada 10,535

Sellers Foundation 9,265

Serono Canada Inc. 7,760

Serotec Ltd. 4,110

Shwachman-Diamond Syndrome Foundation 18,254

SickKids Foundation 31,568,711

SickKids Research Facilities Revenue - external users 400,000

Sigma-Aldrich Canada 3,255

Silicon Graphics Canada Ltd. 254,530

Small Animal Instruments Inc. 64,087

Smith & Nephew Inc. 21,335

Social Sciences and Humanities Research Council of Canada 70,949

Stem Cell Network 70,036

Synx Pharma Inc. 186,539

Tanenbaum Endowment Chair 110,622

Targeted Genetics Corporation 16,589

TEVA Neuroscience, Inc. 2,948

The Arthritis Society 83,580

The Foundation Fighting Blindness - Canada 261,398

The Kidney Foundation 221,459

The Sanfilippo Children’s Research Foundation 50,994

Thermo Crs Ltd 40,674

Transkaryotic Therapies Inc. 225,540

United Mitochondrial Disease Foundation 34,983

University Health Network 59,759

University of Toronto 210,432

Varian Inc. 221,869

Visualsonics Inc. 394,990

VWR International 47,914

Wadsworth Foundation 56,797

Wellcome Trust 69,549

WellSpring Pharmaceutical Corporation 30,000

Wyeth Pharmaceuticals 78,717

Xenogen Corp 120,870

$ 139,729,201



expenses

Operat ions Grants Total

$ 27,621,014 $ 47,748,847 Salaries & Benefits $ 75,369,861

4,639,899 15,588,120 Supplies 20,228,019

14,647,812 3,328,268 Building & Renovations 17,976,080

1,300,000 13,542,115 Equipment 14,842,115

6,039,329 8,700,553 Other 14,739,882

$ 54,248,054 $ 88,907,903 Total $ 143,155,957*

2

3

5

1

4

1. Salaries & Benefits 53% 2. Suppliers 14% 3. Building & Renovations 13% 4. Other 10% 5. Equipment 10%

breakdown of expenses

Philanthropy is a critical source of funding for SickKids, separate and distinct from the funding received from government and granting agencies. Philanthropy, which includes private donations from individuals, families, corporations and foundations, enables SickKids to make needed investments in care, education and research.

the role of phi lanthropy at SickKids

Thank you to all of the donors to SickKids Foundation, and to our government and granting agency partners.

* Expenses greater than revenues covered by funding from prior years


personnel awards to senior scient i f ic staff

CANADA RESEARCH CHAIRS TIER I

2002-2008 Dr. David Bazett-Jones, Cell Biology

2005-2012 Dr. Gabrielle Boulianne, Developmental Biology

2001-2007 Dr. Mark Henkelman*, Integrative Biology

2002-2009 Dr. David Kaplan, Cancer Research

2004-2011 Dr. Amira Klip, Cell Biology

2002-2008 Dr. Howard Lipshitz, Developmental Biology

2005-2012 Dr. Freda Miller, Developmental Biology

2005-2012 Dr. Michael Moran**, Cancer Research

2001-2007 Dr. Martin Post, Lung Biology

2001-2007 Dr. Brian Robinson, Metabolism Research

2005-2012

Dr. Norman Rosenblum, Developmental Biology

2004-2011 Dr. Daniela Rotin, Cell Biology

2004-2011 Dr. Michael Salter, Brain & Behaviour Research

2001-2007

Dr. Philip Sherman, Infection, Immunity, Injury & Repair Research

2005-2012 Dr. William Trimble, Cell Biology

2005-2012 Dr. Shoshana Wodak, Structural Biology & Biochemistry

* shared with Sunnybrook Health Sciences Centre

** based at McLaughlin Centre for Molecular Medicine

CANADA RESEARCH CHAIRS TIER II

2001-2010 Dr. Benjamin Alman***, Developmental Biology

2002-2007 Dr. Benoit Bruneau, Cardiovascular Research

2002-2007 Dr. Brian Feldman, Population Health Sciences

2004-2008 Dr. Paul Frankland, Integrative Biology

2003-2008 Dr. Meredith Irwin, Cancer Research

2004-2008 Dr. Sheena Josselyn, Integrative Biology

2002-2007 Dr. Andrew Paterson, Genetics & Genomic Biology

2001-2006 Dr. Régis Pomès, Structural Biology & Biochemistry

2004-2009 Dr. Lisa Robinson, Infection, Immunity, Injury & Repair Research

2002-2006 Dr. Chetankumar Tailor, Infection, Immunity, Injury & Repair Research

2002-2007 Dr. Lu-Yang Wang, Brain & Behaviour Research

CANADIAN CYSTIC FIBROSIS FOUNDATION

Scholarship Award2003-2005 Dr. Jim Hu, Lung Biology

CANADIAN INSTITUTES OF HEALTH RESEARCH (CIHR)

Senior Investigator (Senior and Distinguished Scientist) Awards2000-2005 Dr. Gideon Koren, Population Health Sciences

2005-2007 Dr. Janet Rossant, Developmental Biology

Investigator Awards2000-2005 Dr. Gabrielle Boulianne, Developmental Biology

2000-2005 Dr. Julie Forman-Kay, Structural Biology & Biochemistry

2001-2006 Dr. Lynne Howell, Structural Biology & Biochemistry

2003-2008 Dr. Stephen Scherer, Genetics & Genomic Biology

2000-2005 Dr. William Trimble, Cell Biology



personnel awards to senior scient i f ic staff - cont inued

New Investigator Awards2003-2008 Dr. John Brumell, Infection, Immunity, Injury & Repair Research

2004-2009 Dr. Lori Burrows, Infection, Immunity, Injury & Repair Research

2004-2009 Dr. Andrew Howard, Population Health Sciences

2002-2007 Dr. Brian Kavanagh, Lung Biology

2003-2008 Dr. Lorelei Lingard, Population Health Sciences

2003-2009 Dr. Anna Taddio, Population Health Sciences

Clinician Scientist Awards2004-2007 Dr. Michael Taylor, Brain & Behaviour REsearch

2003-2006 Dr. William Jeptha Davenport, Brain & Behaviour Research

Research Training Centre Mentoring Fellowship Award 2004-2006 Dr. Robyn Stremler, Population Health Sciences

CIHR INSTITUTE OF GENDER AND HEALTH/ONTARIO WOMEN’S COUNCIL

Mid-Career Award2005-2010 Dr. Gail McVey, Population Health Sciences

CIHR/CANADIAN LUNG ASSOCIATION

New Investigator Award2002-2007 Dr. Wendy Ungar, Population Health Sciences

CIHR/CANCER CARE ONTARIO/ELI LILLY CANADA INC.

Clinician Scientist Awards2003-2007 Dr. Cynthia Hawkins, Cancer Research

2002-2007 Dr. Annie Huang, Cancer Research

CIHR/ONTARIO MINISTRY OF HEALTH AND LONG-TERM CARE

Investigator Award2001-2006 Dr. Teresa To, Population Health Sciences

HEART AND STROKE FOUNDATION OF ONTARIO

Career Investigator Award2004-2006 Dr. Aleksander Hinek, Cardiovascular Research

Scholarship Award1998-2006 Dr. Gabrielle deVeber, Population Health Sciences

NATIONAL CANCER INSTITUTE OF CANADA

Investigator Award1999-2005 Dr. Chi-chung Hui, Developmental Biology

1999-2005 Dr. Jane McGlade, Cell Biology

ONTARIO MINISTRY OF HEALTH AND LONG-TERM CARE

Scholarship Award2005-2010 Dr. Christopher Parshuram, Population Health Sciences

THE ARTHRITIS SOCIETY

New Investigator2002-2006 Dr. Rae Yeung, Cancer Research

THE KIDNEY FOUNDATION

Scholarship Award2004-2006 Dr. Tino Piscione, Developmental Biology

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555 University AvenueToronto, ON, Canada M5G 1X8

For more information about SickKids, please call: Public Affairs: 416.813.5058

For electronic versions of the annual reports, please visit:

www.sickkids.caSickKids

www.sickkids.ca/researchSickKids Research Institute

www.sickkidsfoundation.comSickKids Foundation

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