Research Institute Annual Report 2000-2001 - The Hospital for Sick ...

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Research Institute Annual Report 2000-2001 - The Hospital for Sick ...

Intro theme on page 1

This year saw unprecedented growth in funding

available for health research. Government, granting

agencies and community donors were all committed

to the vision of research improving children’s health.

In this year’s annual report of The Hospital for Sick

Children Research Institute, five case studies illustrate

the role research – at both the bench and the bedside

– plays in improving the health of children in Canada

and around the world.


Message from the director

Annual Report 2000-2001

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Since its inception,

The Hospital for Sick

Children (HSC) has viewed

as one of its principal

missions “to treat the

children of tomorrow

better than we treat the

children of today”.

To accomplish this goal, HSC

has continuously invested a portion

of its resources for research, as

the best way to develop better

treatments. The investment in

research pays off by having a trained

work force that can assess and

implement novel treatments

developed elsewhere. If an institution

does not make the commitment

to carry out research itself, it ends

up “buying last year’s model at

twice the price” because it lacks

the expertise to appropriately size

up new ideas and products.

The HSC investment in research

took form in the mid-1950s when

the Research Institute was established.

Subsequently, during the

1970s and 1980s, the number of

researchers, especially those doing

laboratory-based work, increased

significantly. In the 1990s, the

challenge was to facilitate patientbased

research, to complement

the laboratory-based research, a

task that I believe we have largely

accomplished. For example, we

have established categories of

appointments to the Research

Institute that include all researchers,

regardless of their scientific or

professional background. As a

result, all researchers are now supported

by the infrastructure of the

Research Institute, regardless of

which department in the hospital

they are appointed to. We have also

established training opportunities

for individuals with a variety of

research and professional interests.

Having made these investments

over a 50-year period, HSC is now

among the leading institutions

contributing to the remarkable

advances in health research taking

place around the world.

HSC’s ability to improve patient

care through research is founded

on a number of factors. First, we

have established an excellent

relationship with our patients

and families and they willingly participate

in many research projects.

They recognize that even if a

particular project may give them

only a small benefit, the knowledge

that will be gained will help the

children of tomorrow, not just here

but throughout the world.

Second, we have within our walls

a staff with unparalleled expertise

and credentials. It is a well-known

truism that quality begets more

quality. At HSC, we notice that

recruiting individuals of quality

is made easier because many

such individuals are already here.

New members of the research

and clinical community at HSC are

attracted to our institution because

they realize that having outstanding

colleagues is going to help them

with their own aspirations.

Third, because we look after a

wide range of clinical problems, our

research is extremely broadly based.

This allows us to assemble interdisciplinary

research groups that can

tackle complex and difficult questions

from both basic science and

clinically applied perspectives.

Fourth, HSC has been fortunate

to have financial and fundraising

support from innumerable

volunteers and professionals.

Over the past 20 years, more

than $500 million has been raised

to advance research at HSC.

These resources have allowed us

to set up internal systems to foster

research. For example, we run

annual funding competitions to

support research trainees and to

enable researchers to test new

ideas before competing externally

for grants. We also subsidize a

variety of research services, such

as biostatistical and epidemiological

consultations, laboratory glasswashing

and computer support.

Fifth, our internal resources

enable us to bring new sciences

to HSC and continually evolve

our research. We accomplish this

by recruiting researchers working

in new fields and providing them

with the new equipment necessary

for their work. Two examples of

the moving frontier of science

are the development of genome

sciences and the application of

imaging physics to biological

problems. During the past few

years we have recruited scientists

in both of these fields to HSC.

They, in turn, are developing

collaborations with clinician

researchers with practical

problems to solve.

The case studies in this report

illustrate how research at HSC

improves patient care. Our ability

to make this impact is due in

large part to the unique research

environment that we have created.

Our outstanding clinical professionals

and top-calibre researchers

are well supported and they have

the opportunity to work together

on a broad range of health issues.

Our future challenge is to maintain

this productive environment.

What will this require? I believe

that the most important element

for our continued success will be

our ability to retain our outstanding

researchers by providing them with

state-of-the-art equipment and

facilities. This is becoming a

problem at HSC because our

success in peer-reviewed funding

competitions is placing an increasing

burden on our research space. If a

solution to this problem is not

forthcoming, many scientists will

be attracted to other institutions

that promise new facilities, to the

detriment of our patients and their

long-term needs.

We will also need to be proactive

rather than reactive in developing

our internal processes to respond

to the increasing external demands

for accountability. This is happening

because funding and regulatory

agencies are demanding stricter

guidelines and procedures. While

in this regard HSC is currently

well positioned after developing an

integrated set of research policies,

we will need to establish a better

administrative framework. If we

are successful, this will mean that

our investigators will have better

internal support in meeting their

obligations to the community that

funds their work.

Notwithstanding the challenges,

I believe that the research community

at The Hospital for Sick

Children will continue to thrive,

and that our work will lead to

better outcomes for our patients

and their families.

Manuel Buchwald, OC, PhD, FRSC,

Director, Research Institute and Chief of

Research, The Hospital for Sick Children;

Lombard Insurance Chair in Paediatric

Research, University of Toronto and

The Hospital for Sick Children;

Professor, Department of Molecular and

Medical Genetics, University of Toronto

Notwithstanding the challenges,

I believe that the research community

at The Hospital for Sick Children will

continue to thrive, and that our work

will lead to better outcomes for our

patients and their families.

– Dr. Manuel Buchwald

Manuel Buchwald

Research Institute

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cancer research

Annual Report 2000-2001 Childhood

4

Dr. David Malkin, an oncologist and scientist,

examines six-year-old Tyler in HSCÕs oncology clinic.

Childhood cancer was once thought to be nearly

incurable. Today, while most young people with

cancer can be cured with existing therapies, up

to 30 per cent will die from the disease. Cancer

remains the number one disease-related cause

of death in children.

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Cancer research

Annual Report 2000-2001

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At The Hospital for Sick

Children (HSC), clinicians

and researchers continue

the quest to find better

treatments. As the

second largest paediatric

oncology program in

North America, Sick Kids

sees roughly 300 new

cancer patients every

year. Despite the

increasing survival rate,

many challenges lie ahead

to ensure children with

cancer are able to have

a better quality of life

during treatment, as well

as afterwards, when the

child grows into

adulthood.

As director of HSC’s New Agent

and Innovative Therapy (NAIT)

program, oncologist Sylvain

Baruchel is occupied with developing

clinical trials for drugs and

biological agents that are more

effective and less toxic than

current therapies, and that

will protect children from the

complications of chemotherapy.

“Our goal is to increase the

number and range of anti-cancer

agents and find ways to improve

the quality of life for children

undergoing treatment for

cancer,” explains Dr. Baruchel.

New cancer treatments must

go through a rigorous process

of many stages of testing before

they are considered safe and

effective for patients. Beyond in

vitro (cells) and in vivo (animal)

testing, new interventions must

also go through three levels of

clinical trials. Phase 1 trials

determine a safe and appropriate

dose of the treatment. Phase 2

trials test the effectiveness of the

treatment on specific malignancies.

Phase 3 trials confirm the

effectiveness of the treatment

on a large number of patients in

comparison to existing therapies.

Under Dr. Baruchel’s direction,

HSC is now heading up the paediatric

Phase 1 clinical trials of

low-dose chemotherapy (vinblastine)

in association with drugs

that target blood vessels (antiangiogenic

agents). In animal

studies, a daily schedule of this

pharmaceutical combination

caused tumours to regress.

The severity of current cancer

treatments has also pushed HSC

surgeons Benjamin Alman and

Christopher Forrest into basic

science research.

“Most of my research focuses

on musculoskeletal tumours. As

an orthopaedic surgeon, I often

have to perform very invasive

surgery on children with these

tumours. This is what has driven

me to study the underlying biology

of what causes these tumours

to develop,” says Dr. Alman.

Musculoskeletal tumours

(tumours of the bone, joints, and

soft tissues) occur in five per cent

of the population. Dr. Alman’s

lab is looking at the role that

developmental signalling pathways

play in the creation of

musculoskeletal tumours.

Developmental signalling

pathways are important during

normal human development

where different cells’ signalling

pathways are ‘turned on and off ’

in a coordinated manner.

Normally, these pathways are

‘turned off ’ when growth is complete

and are not activated except

during pathological conditions,

such as when a cut on the skin

must heal. In musculoskeletal

tumours, the developmental

signalling pathways get ‘turned

back on’ again.

Researching developmental

signalling pathways is very

important because there are

many agents known

to block these pathways that

could be potentially used as

novel therapeutic approaches

in treating these tumours,”

says Dr. Alman.

Dr. Christopher Forrest, a craniofacial

surgeon, is examining

potential new treatments for the

side effects of the radiation used

to treat head and neck cancer.

Children are surviving cancer,

but the radiation they receive

to combat the disease can

severely retard bone growth,

leading surgeons, such as

Dr. Forrest, to perform plastic

surgery for craniofacial deformities.

Research in Dr. Forrest’s

lab is focused on preventing

radiation-induced inhibition of

bone growth. He is using an

animal model to test the use of

radioprotective agents to alleviate

this side effect.

Oncologist David Malkin is also

involved with cancer research,

but at the molecular level. He

studies the genetics of familial

cancers and looks at the role

genes may play in children’s

predisposition to different types

of cancers. In particular, he has

been studying the p53 gene,

a gene we all have in every cell

in our bodies. If the p53 gene

becomes altered, its cell can

become cancerous. Dr. Malkin’s

lab previously identified that

individuals carrying altered p53

genes are at a higher risk of

developing cancer.

“This type of research can lead

to the development of predictive

genetic testing for children or

adults that may be at risk of

developing cancer. It could also

give us the opportunity to test

unaffected relatives and then

potentially look for ways of early

detection,” says Dr. Malkin.

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Annual Report 2000-2001

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Pain research

Clinical nurse specialist Sharyn Gibbins examines a

premature infant in HSCÕs neonatal intensive care unit.

From the sharp agony

of a sudden headache

to the relentless throb

of a sore back, everyone

is familiar with what

pain can feel like.

Unfortunately for some

children, coping with

pain is an excruciating

ordeal they face on a

frequent basis.

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Pain research

Annual Report 2000-2001

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Despite the discomfort,

sensing pain is one way

the human body alerts

the brain that it’s dis-

tressed. Sick Kids senior

scientist Michael Salter

is working to understand

the mechanisms of pain

on a molecular basis;

in particular, in the cells

that process, modulate,

and transmit pain infor-

mation in the spinal cord.

“In the nervous system, for

sensations that come from your

skin, muscle, heart, gastrointestinal

track, and everything in the

periphery, you have special

receptor cells that are specifically

stimulated by pain-producing

stimuli or ‘noxious stimuli’.

These nerve cells detect noxious

stimuli and transmit the information

to the spinal cord. In

the spinal cord there is a network

of cells that sends information

to the brain, to areas where the

experience of pain is created,”

Dr. Salter explains.

Dr. Salter’s research examines

the signal transduction pathways

involved in either facilitating

or depressing pain transmission

in nerve cells. One area his lab

is examining in detail is the

glutamate transmission system.

Glutamate is one of the main

neurotransmitters which cause

nerve cells to become ‘excited’

and generate action potentials

(cells sending out signals to each

other). Identifying and mapping

the communication of the nerve

cells to the spinal cord, and consequently

the brain, is one way

Dr. Salter hopes to develop a

better understanding of how

pain is processed.

Eventually, this may lead to

the development of drugs that

could help counteract both acute

and chronic pain. “Those of us

working in this area have a vision

that what we are doing will have

direct relevance to what happens

to patients. By figuring out new

ways to suppress abnormal pain

signalling to the brain without

affecting other sensations or

cognitive functions, we will be

able to design new therapies that

stop pain but don’t produce the

side effects associated with present

treatments,” says Dr. Salter.

Applying pain research to bedside

practice is also a goal that

HSC senior scientist Bonnie

Stevens is striving to achieve.

Her clinical studies involving

pain research were among the

first to identify how infants

express pain. This discovery in

the early 1990s led to the development

of several infant pain

assessment measures that

triggered a major shift in the

thinking of health professionals,

resulting in the use of various

strategies to manage pain in

infants and children receiving

diagnostic and therapeutic

procedures.

Currently, her work continues to

explore the best pain assessment

measures, and how these can

be used to determine the effectiveness

of pharmacological,

behavioural, and environmental

interventions that may eliminate

pain. Along with identifying the

most effective pain relieving

strategies, Dr. Stevens is studying

the impact of consistent use

of interventions on patient and

economic outcomes.

“When you take all these factors

into account, then perhaps we

can begin to figure out what it

is that would either stand in the

way of, or facilitate, the uptake

of research knowledge into

practice,” says Dr. Stevens.

Dr. Bonnie Stevens, holder of the Signy Hildur Eaton Chair in

Paediatric Nursing Research at The Hospital for Sick Children.

The studies reflect Dr. Stevens’

interest in the immediate and

long-term consequences of pain

in infants that have long hospitalizations

in the neonatal

intensive care unit and require

multiple painful procedures.

Dr. Anna Taddio, HSC pharmacist

and associate scientist, has

focused on evaluating the safety

and efficacy of medications for

painful procedures in infants.

“It is very important to have

proper studies done in this

population so that we gain the

expertise needed to use these

medications in the best way

possible,” says Dr. Taddio.

Recent studies have determined

the effectiveness of anaesthetic

creams such as EMLA and

Ametop during procedures

on infants.

Dr. Taddio has also been investigating

the long-term effects of

pain on infants. She was the

first to demonstrate that untreated

newborn circumcision pain has

long-term effects on infant pain

behaviours four to six months

after the procedure and that

using local anaesthetics during

circumcision to prevent pain can

minimize these long-term effects.

Now her work is branching

out into learning whether infants

are able to anticipate pain.

“In particular, we are looking

at babies who receive repeated

painful procedures and we

are asking: Do they learn to

know when someone is about

to perform a painful procedure

on them and do their responses

to painful procedures increase

over time? If our results are

positive, we can start thinking

about ways to help infants

interpret their environment

and strive to ease their anxiety

as well as their pain.”

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Annual Report 2000-2001 ADHD

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research

In today’s society, the term attention

deficit hyperactivity disorder (ADHD)

is commonly used to describe

children who display developmentally

inappropriate and impairing levels

of restless and impulsive behaviour

or inattentive and disorganized

behaviour, or both. Attention deficit

hyperactivity disorder is a prevalent

problem. Even the most conservative

estimates indicate that it occurs in

three to five per cent of school-age

children and adolescents. It typically

is evident during pre-school years

and often persists into adulthood.

Dr. Michael Noseworthy, MRI physicist, prepares Marielle, 5, for the MRI.

Functional MRI is being used as part of a new research study on ADHD.

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ADHD research

Annual Report 2000-2001

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Attention deficit

hyperactivity disorder

is associated with

difficulties at every stage

of life, from difficulties

with socialization

and learning in children

and teenagers to problems

with relationships,

employment, and

parenting as adults.

The widespread use of

medications such as Ritalin

to counteract some of the

symptoms of ADHD has

sparked public controversy.

It is estimated that roughly

two million children in North

America receive some form

of stimulant medication.

However, the use of medications

as a treatment for ADHD is

only one piece of the puzzle.

At The Hospital for Sick

Children, researchers are tackling

the disorder from a number of

angles. Sick Kids senior scientist

Rosemary Tannock looks at the

mechanisms that underlie the

behavioural issues defining

ADHD and notes a number

of shifts in thinking from 20

years ago. The current models

approach the issue from a

developmental standpoint

Dr. Michael Noseworthy and Dr. Russell Schacher with Marielle, 5.

rather than viewing it as strictly

a socialized phenomenon as it

was in the past.

There are marked overlaps

between ADHD and other

developmental disorders such as

reading or learning disabilities

and language impairment. The

overlap of disorders could be

as high as 60 per cent. It is

puzzling why this occurs and

we are focused on trying to

understand whether there are

common cognitive characteristics

underlying ADHD, language

impairments, and reading disabilities

that could account for

the overlap,” says Dr. Tannock.

Part of the process involves

defining appropriate treatments

for the cognitive deficits of

ADHD (the problems ADHD

patients experience with their

thinking skills) and understanding

the impact of these treatments

for the patient. Ritalin, for

instance, has been found to

have no effect on the cognitive

deficits of some disorders, such

as dyslexia, but it can improve

patients’ attention, monitoring

of task performance, and ability

to regulate their actions. Finding

treatments is especially imperative

for children with both

ADHD and reading disorders,

who may be shuffled around

in the educational and health

care systems without gaining

the optimum treatment and

learning strategies.

Dr. Tannock, along with HSC

senior scientist Maureen Lovett

and other colleagues at Sick

Kids and The Toronto Board of

Education, have designed and

implemented academic remediation

programs for children with

ADHD and reading disorders.

Developing a practical form of

treatment and closely studying

the outcomes are two of the

primary goals. “Each child participating

is monitored carefully

to allow us to evaluate the results

of taking the reading program

versus a non-reading program,

with and without stimulant medication,”

explains Dr. Tannock.

HSC senior scientist Russell

Schachar is also involved in

identifying the cognitive deficits

in ADHD. “We have had tremendous

success in this regard and

have delineated a number of

cognitive deficits. We are particularly

known for our research in

deficits in inhibitory control –

the ability to stop what you are

doing smoothly and efficiently,

like when you stop your swing

for a badly pitched ball,” says

Dr. Schachar. Children with

ADHD have trouble with this

function and inhibitory control

seems to be a marker for the type

of brain-based cognitive deficits

they have. This is significant in

that it can inform diagnostic

practice and treatment studies.

Recently, Dr. Schachar and Sick

Kids MRI physicist Michael

Noseworthy received funding to

study ADHD patients and non-

ADHD individuals performing

tasks requiring inhibitory control,

using neuroimaging to

document the responses in the

brain. The study will focus on

ADHD children on stimulants,

such as Ritalin, and off stimulants

to see the nature of their

deficit through both the brain

mechanism and action of the

drug they are taking. Using

state-of-the-art MRI, in

conjunction with fibre-optic

visual presentation hardware

that allows patients to view a computer

or VHS video while being

scanned, functional MRI (fMRI)

scans are performed. The special

fMRI scan, called blood oxygen

level dependent (BOLD) imaging,

allows regions of activated brain to

be located and mapped.

The signals we are detecting are

due to minute differences in the

ratio between deoxyhaemoglobin

and oxyhaemoglobin. When an

area of the brain is activated,

there is increased regional blood

flow but also a disproportionate

extraction of oxygen from the

blood, and the special kind of

imaging we do is sensitive to this

change. We see an increase in

signal in the BOLD image and

we process the data and overlay

the activated pixels overtop of

the anatomic images,” explains

Dr. Noseworthy. “The ADHD

study is the first psychiatric study

with fMRI at Sick Kids. It is

opening the door to studying

psychological disorders as

well as neuropathologies with

imaging technologies.”

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Annual Report 2000-2001

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Diabetes research

Dr. Denis Daneman, endocrinologist and senior associate

scientist, sees Matthew, 11, in the Sick Kids diabetes clinic.

The discovery of insulin in 1921 by Dr. Frederick

Banting and Dr. Charles Best at the University

of Toronto changed the face of diabetes

treatment. Now, almost 80 years later,

people with diabetes – though not rid

of the complications of the disease – live

fuller lives and have marked improvements

in the quality of their care.

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Diabetes research

Annual Report 2000-2001

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“What has happened over

the years is a large series

of refinements in care,”

says endocrinologist

Denis Daneman. “If you

look at the morbidity

and mobility of diabetes,

it has changed.”

Continual modifications have

meant improvements such as

more purified insulin, patient

self-monitoring of blood glucose

levels, and the ability of a physician

to measure haemoglobin

A1C, which helps to measure

long-term diabetes control on

a three-month basis rather than

a minute-by-minute basis.

Along with new methods and

devices for treating diabetes,

clinicians now have greater

knowledge of diagnosing early

complications of diabetes, such

as eye and kidney damage.

At Sick Kids, clinical advancements

continue to push the

level of understanding and care

forward. Clinical research has

gone in a number of directions,

including involvement in a large

multicentre study – the Diabetes

Control of Complications Trial –

from 1982 to 1993. “The trial

had an incredible effect on how

we treat diabetes. We have

ratcheted up the heat in terms

of the intensity of therapy for

people with type 1 diabetes. It

has become important to achieve

and maintain the best possible

control to minimize the

risks and complications,”

says Dr. Daneman.

Other HSC clinical studies

focus on factors contributing

to or hindering diabetes care,

such as metabolic and psychological

factors. Researchers are

also looking for early markers

of diabetes in order to assess

whether patients can be

diagnosed earlier for their

susceptibility to developing

complications, particularly

kidney disease.

With a clinic population of

close to 1,000 children and

adolescents, Sick Kids is continually

involved in different studies

that help redefine best practices.

“It’s our responsibility not only

to provide our patients with

the best standard of care, but

to ensure at all times that we

are pushing that standard of

care to be better and better,”

adds Dr. Daneman.

Parallel to the efforts of clinical

researchers, Sick Kids bench

scientists are striving to understand

the basics of the disease.

Senior scientist Amira Klip is

focused on studying the problem

at the cellular level. Diabetes is

actually two diseases, designated

as type 1 and type 2, with

similarities and differences in

their manifestation. One of the

hallmarks of type 2 diabetes is

insulin resistance, which can also

accompany type 1 to a milder

degree. In order to understand

the process of insulin resistance

more effectively, Dr. Klip studies

insulin action and the cellular

and molecular steps involved in

this process.

“We are in the business of

understanding the biology of the

cell. In order to move on to what

‘is’ diabetes you must understand

the basic mechanism of action

of insulin,” says Dr. Klip. In the

lab, muscle and fat cells are grown

in culture, which are typically the

cells that respond to insulin in

the body. Identifying the multiple

steps of insulin action and

mapping this process of intercellular

signalling and intracellular

traffic (how the glucose transporters

move to the cell surface)

will help contribute to an overall

understanding of insulin resistance.

Eventually, the knowledge

gained could lead to the creation

of drugs designed to chemically

replace these specific steps that

are altered with diabetes.

In another part of the Research

Institute, senior scientist Jayne

Danska is preoccupied with

identifying the genetic make-up

of the disease. With the aid of

a mouse model with type 1

diabetes, her lab has made great

strides in understanding the

early stages of progression

towards the disease. Using

these early steps, they will try

to identify the genes that control

these stages.

The logic is, if you can focus on

a little piece of the progression

of the disease, perhaps then you

can get the kind of quality of

information that you need, and

begin to find a couple of genes

that control just that step,” says

Dr. Danska.

The results so far have been

encouraging. Her research team

has been able to identify early

features in the mouse model that

are extremely useful in genetic

analysis, allowing them to focus

on just a few regions of the

genome containing the genes

controlling the early progression

of the disease. Due to the similarities

between the genetic

composition of the mouse

genome and the human genome,

finding these results in the

mouse model will narrow down

the search for the human genetic

regions immensely.

“Now in the post-genomic era, we

have the ability to accelerate the

pace of our discoveries, and we

have an unparalleled opportunity

to use animal models in a very

powerful way,” says Dr. Danska.

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Annual Report 2000-2001

20

Congenital malformation

research

The majority of the time, nature has the wonderful

ability to reproduce with exact symmetry and form.

Unfortunately, part of the human condition includes

the possibility of being born with a congenital

malformation of some kind.

Three-year-old Kassandra, a patient

with Beckwith-Wiedemann syndrome,

visits with Dr. Rosanna Weksberg.

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Congenital malformations

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Every pregnancy includes

a baseline risk (a two

to three per cent chance

of having a baby with a

birth defect) despite

an expectant mother’s

best efforts to live a

healthy lifestyle. While

factors contributing to

this may be genetic or

environmental, in many

instances the reasons are

still unknown.

The devastation that the drug

thalidomide caused unborn children

back in the 1960s forced

society to pay closer attention

to the elements that contribute

to birth defects. Researchers

have since identified that exposure

to a number of substances,

including specific drugs, alcohol,

and organic solvents, can result

in congenital malformations.

However, a genetic anomaly

underlies many congenital

malformations, and much more

research is required to uncover

the answers.

As both a clinical geneticist and

researcher, Sick Kids senior

associate scientist Rosanna

Weksberg is in a unique position

to analyze a group of disorders

called overgrowth syndromes.

Her research is centred on

Beckwith-Wiedemann syndrome

(BWS) and Simpson-Golabi-

Behmel syndrome (SGBS), two

conditions in which children are

born larger than expected and

which are associated with a

predisposition to developing

cancers. Children with BWS

have a 7.5 per cent risk of

tumour development in the first

eight years of life. In some cases,

the syndromes may also result in

congenital malformations such

as an enlarged tongue or the

protrusion of internal organs on

the outside of the body.

What began as a search for the

genes involved in causing BWS

has become a more complicated

process. It is known that a series

of genes causing the syndrome

are located on chromosome 11.

Dr. Weksberg is seeking to

understand the unusual regulation

of this genetic region more

precisely and also to study how

the genes contribute in different

ways to the development of

the condition.

Her lab obtains blood and tissue

samples from children with

BWS and then tries to work out

the molecular changes associated

with both the syndrome and the

development of cancer. “We are

classifying children according to

what their molecular alterations

are to see who are at highest risk

for tumour development, and to

see if we can identify the children

who are going to develop

tumours,” explains Dr. Weksberg.

Sick Kids senior scientist

Chi-chung Hui is also interested

in the scientific problems

presented with congenital

malformations. Through the use

of mouse models, his lab studies

a number of genes and the

development of malformations

associated with these genes

when they are mutated. Understanding

why congenital

malformations occur is the type

of basic question he is interested

in answering.

A number of defects are analyzed

including malformations

in limb or digit development,

lung development, cleft palates,

and imperforate anuses. The

models are useful in showing

the genetic-makeup and demonstrating

the developmental

process resulting in the defect.

“Often our starting point is that

we have a gene that is likely to

be important but we are unsure

of its function. We then generate

a mouse model that lacks this

gene or contains a modification

of this gene in order to directly

assess and establish its function,”

explains Dr. Hui.

With the completion of the

DNA sequence of the human

genome, Dr. Hui feels it is

essential to make use of this

body of information towards

medical application. “Although

at the moment this information

may not solve all of our

problems basic research is a

knowledge-generating mechanism.

We generate knowledge

and hopefully the future generation

will use it to create better

solutions for these types of problems,”

says Dr. Hui.


2000Ð2001 Research Institute highlights

Annual Report 2000-2001

24

Major research

advances

Cardiovascular research

Research conducted at The

Hospital for Sick Children

(HSC) has opened up the possibility

for a new treatment for

pulmonary hypertension that

may also be applicable to all

types of blood vessel obstruction.

Researchers in Dr. Marlene

Rabinovitch’s lab were able

to completely reverse fatal

pulmonary hypertension in an

animal model using an elastase

inhibitor. Not only did it stop

the progression of the disease,

but the blood vessel reverted

to a normal condition. Elastase

is an enzyme that causes cells in

blood vessels to rapidly divide,

so that the vessel becomes

obstructed.

Neurodegenerative diseases

research A team of researchers

led by HSC senior scientist

Roderick McInnes has learned

more about how neurons die in

inherited neurodegenerative

diseases such as Huntington’s

and Parkinson’s. Previously, it

was believed that mutated genes

in the inherited conditions

caused cumulative damage to

the neurons, damage from which

they eventually died, much like

how the aging process leads to

death in humans. However, this

study showed that neurons are

healthy until the time they die,

and if they can be saved by new

treatments to be developed, they

will be able to function normally.

Genetics research An international

team of researchers,

including scientists from Sick

Kids and the University of

Toronto, identified the gene

responsible for a form of kidney

disease — distal renal tubular

acidosis — and the corresponding

diagnostic test.

A group of scientists from

Canada and the United States,

including HSC senior scientist

Johanna Rommens, identified

a gene that leads to inherited

prostate cancer. The ELAC2

gene is the first prostate cancer

susceptibility gene to be identified

from family-based studies.

The study culminates more

than 10 years of work with

families at high risk of prostate

cancer. Men who carry one of

the high-risk ELAC2 mutations

are five to 10 times more likely

to get prostate cancer than other

men. Men who carry the moderate-risk

forms of the gene are

1.5 to three times more likely to

get the disease than other men.

Dr. Stephen Scherer and

post-doctoral fellow Kazuhiko

Nakabayashi discovered what

is possibly the largest gene in

the human genome, with 100

times the chemical agents than

the average gene. It is suspected

that this gene, found on chromosome

7, contains instructions

to build the framework of the

human brain.

Asthma research Sick Kids

researchers found that children

experiencing a severe asthma

attack are far better off taking

oral steroids than inhaled versions

of the drugs. Dr. Suzanne Schuh

and colleagues found that

treatment with oral steroids led

to far fewer hospitalizations and

significantly better lung function.

The Childhood Asthma

Management Program (CAMP),

a five-year, eight-centre study

funded by the National Heart,

Lung, and Blood Institute

(NHLBI) of the National

Institutes of Health in the

United States, found that

inhaled corticosteroids are safe

and effective for the long-term

treatment of children with mild

to moderate asthma. Sick Kids

is the only Canadian centre

participating in CAMP, the

longest and largest controlled

study of treatments for

childhood asthma to date.

Cancer research Dr. Sylvain

Baruchel, head of the New

Agent and Innovative Therapy

Program, was a collaborator on

research by Dr. Robert Kerbel

of Sunnybrook and Women’s

Health Sciences Centre, which

showed that, in animals, using

low doses of the chemotherapy

drug vinblastine on a daily

schedule along with drugs

that target blood vessels (antiangiogenic

agents) tumours can

regress. Dr. Baruchel is now

heading up the paediatric Phase

1 clinical trials of this research.

Stem cell research A team of

HSC researchers led by senior

scientist John Dick has discovered

that distinct types of stem cells

exist within the blood system

that differ in the length of time

they can sustain a stem cell transplant.

They have been termed

short-term repopulating and longterm

repopulating stem cells.

Most applications require that

stem cells function for many

years following transplantation.

Therefore, the long-term

repopulating stem cells would be

the ones researchers would want

to target when permanent

replacement is important, such

as in the development of new

treatments, like gene therapy

and stem cell expansion. There

may also be applications for the

short-term repopulating stem

cells, which allow for a robust

but temporary graft following a

stem cell transplant.

Motherisk research

Researchers in HSC’s Motherisk

Program have found the benefits

outweigh any potential risks for

pregnant or breastfeeding

women taking medications for

depression.

In another study, Motherisk

researchers concluded that

exposure during pregnancy

to Dextromethorphan (DM),

an active ingredient present in

a variety of cough and cold

remedies, does not increase the

chances of major birth defects.

The first prospective study

on the use of echinacea during

pregnancy, led by the Motherisk

Program in collaboration

with the Canadian College of

Naturopathic Medicine, found

no increased risk for major

malformations.

Health services research

Researchers at Sick Kids and the

Institute for Clinical Evaluative

Sciences published two reports

on the inpatient and outpatient

services provided to Ontario’s

children from 1992–1998.

They found an overall trend that

children are admitted to hospital

less frequently than in the past,

except for infants with jaundice

and teenagers with psychiatric

disorders. They also found that

OHIP billings for paediatric

outpatient services declined

by 11 per cent leading to a

reduction in government

expenditures of 5.7 per cent.

Transplantation research

A research team lead by HSC

cardiologist and scientist Lori

West discovered that infant heart

transplants can be performed

safely and successfully despite

major blood type incompatibility

between the donor and recipient.

This finding challenged accepted

clinical thinking about the human

immune system and offers new

hope for infants waiting for heart

transplantation.

Multiple sclerosis research

A team of researchers led by

HSC senior scientist Michael

Dosch determined that multiple

sclerosis (MS) and type 1

(juvenile) diabetes mellitus are

far more closely linked than

previously thought, including

the role cow milk protein plays

as a risk factor in the development

of both diseases for people

who are genetically susceptible.

Sick Kids neurologist Brenda

Banwell developed a national

registry that will track the

progression of multiple sclerosis

in children, allowing researchers

to better understand paediatric

MS. The data gathered will

also be used to design future

trials for the evaluation of the

efficacy and safety of therapies

in this patient population.

Research Institute

25


2000Ð2001 Research Institute highlights

Annual Report 2000-2001

26

New initiatives

and activities

Ontario Centre for Genomic

Computing Ontario Energy,

Science, and Technology

Minister Jim Wilson announced

a commitment of more than

$8 million to create the Ontario

Centre for Genomic Computing

(OCGC) at The Hospital for

Sick Children. The OCGC

will provide the Ontario research

community with ready access

to biological data, software and

hardware, including two supercomputers.

This funding is part

of the Challenge Fund’s Ontario

Genomics Initiative. SGI

Canada is the private sector

partner in this venture.

Celera Genomics database

Sick Kids was the first Canadian

institution to gain access to the

Celera Genomics database.

Access to Celera’s comprehensive

genomic information, as well as

its advanced tools and software,

will help HSC researchers

identify disease-causing genes,

opening the door for improved

diagnosis and treatments

for disease.

Leading-edge research

policies Following recommendations

from the Naimark

Report (November 1998) and

the Research Policy Task

Force Report (Macleod Report,

September 1999), HSC’s

research policies were reviewed.

As part of this review, a number

of key research policies were

revised or developed and are

now in effect. These policies

provide guidelines for research

activities for an increasingly

complex climate and are a measure

of public accountability.

Recognizing granting

agencies The HSC Research

Institute has initiated a program

to recognize the contributions

of Canada’s major granting

agencies to research at Sick Kids.

Last year, the support from the

Canadian Cystic Fibrosis

Foundation (CCFF) and the

National Cancer Institute of

Canada (NCIC) was recognized

by the HSC Research Institute

with special events and plaques

that hang in the Research

Institute. Other agencies will be

recognized in the coming years.

Since its establishment in 1960,

the CCFF has contributed

more than $30 million to cystic

fibrosis research at Sick Kids.

Since 1994, $17,565,812 has

been granted to HSC scientists

from the NCIC, the researchgranting

arm of the Canadian

Cancer Society and The Terry

Fox Foundation.

New Mouse Imaging Facility

Sick Kids was awarded grants

from the Canada Foundation

for Innovation ($5,294,947)

and the Ontario Innovation

Trust ($5,294,947) to construct

Canada’s first Mouse Imaging

Facility. The Hospital for Sick

Children Foundation is

providing the matching funds

for HSC’s share of the project

(20 per cent of the total).

Dr. Mark Henkelman, senior

scientist, Integrative Biology,

will head up this project that

will use state-of-the-art imaging

technologies with mouse models

of human genetic disease.

Awards and

recognition

Canada Research Chairs

Six HSC researchers were

among the recipients of the

first round of Canada Research

Chairs (CRCs).

Tier I CRCs Seven-year

renewable chairs for experienced

researchers who are acknowledged

by their peers as world

leaders in their fields:

❙ Mark Henkelman, senior

scientist, Integrative Biology

❙ Martin Post, head and senior

scientist, Lung Biology

❙ Brian Robinson, head and

senior scientist, Metabolism

Research

❙ Philip Sherman, senior

scientist, Infection, Immunity,

Injury & Repair Research

Tier II CRCs Five-year chairs,

renewable once, for researchers

who are acknowledged by their

peers as having the potential

to lead in their fields:

❙ Ben Alman, scientist,

Developmental Biology

❙ Régis Pomès, scientist,

Structural Biology and

Biochemistry

The Canada Research Chairs

Program was created as part of

the 2000 Federal Budget when

$900 million was allocated to

help Canadian universities

attract and retain the best

researchers and achieve research

excellence in health, natural

sciences, technology, social

sciences and humanities. Two

thousand Canada Research

Chairs will be established by

May 2004.

Cancer research awards

Dr. John Dick, senior scientist,

Cancer and Blood Research,

received Canada’s most prestigious

cancer research award, the

Robert L. Noble Prize. Awarded

by the National Cancer Institute

of Canada, the Robert L. Noble

Prize recognizes outstanding

achievements in cancer research.

Dr. Dick was honoured with this

award for his research that has

enhanced the understanding of

leukaemia, and opened the door

for the development of new

treatments.

Dr. Chi-chung Hui, a senior

scientist in Developmental

Biology, was also honoured by

the National Cancer Institute

of Canada. Dr. Hui received

the Terry Fox Young Investigator

Award, which recognizes a

promising young investigator

doing outstanding basic

laboratory research. Dr. Hui’s

work has greatly increased the

understanding of the biological

process by which cancer

develops.

Signy Hildur Eaton Chair in

Paediatric Nursing Research

Dr. Bonnie Stevens was

appointed the inaugural holder

of the Signy Hildur Eaton

Chair in Paediatric Nursing

Research at The Hospital for

Sick Children. Dr. Stevens has

an established reputation as a

leader in the field of pain

research in neonates and

children, and as holder of the

endowed chair, she will continue

to conduct patient-focused

research on pain assessment

and management in infants and

children, while working to

strengthen a nursing culture that

values research-based practice.

This chair, made possible

through a generous philanthropic

gift of $2 million from the

Eaton family through The Eaton

Foundation, is the first of its

kind in Canada focusing on

paediatric nursing research.

CIHR personnel awards

The following HSC scientists

received personnel awards in the

March 2001 competition of the

Canadian Institutes of Health

Research (CIHR):

❙ Dr. Lynne Howell, Structural

Biology and Biochemistry,

Investigator Award

❙ Dr. Yu Tian Wang, Brain

and Behaviour Research,

Investigator Award

❙ Dr. Benoit Bruneau,

Cardiovascular Research,

New Investigator Award

PREA awards In 20002001,

seven HSC scientists were

recipients of the Premier’s

Research Excellence Awards.

The awards recognize excellence

in investigators, who are within

eight years of their careers

as independent scientists.

The recipients were: Dr. Jayne

Danska, Developmental Biology;

Dr. Jane McGlade, Cell Biology;

Dr. Daniela Rotin, Cell Biology;

Dr. Abhijit Guha, Cancer and

Blood Research; Dr. Johanna

Rommens, Genetics and Genomic

Biology; Dr. Yu Tian Wang,

Brain and Behaviour Research;

and Dr. Chi-chung Hui,

Developmental Biology.

Dr. Gabrielle Boulianne,

Developmental Biology, was

selected as the recipient of the

Genetics Society of Canada

Young Scientist Award. The

award recognizes the contributions

Dr. Boulianne has made in

the field of genetics since she

completed her first degree.

Research Institute

27


2000Ð2001 Research Institute highlights

Dr. Anthony Chan, a scientisttrack

investigator in Integrative

Biology, was the recipient of

the newly-established Canadian

Paediatric Society (CPS)

Research Award.

Dr. Charles Deber, senior scientist

in Structural Biology and

Biochemistry, received the 2000

Vincent du Vigneaud Award,

presented by the American

Peptide Society in recognition

of outstanding achievements in

peptide and protein research.

Dr. Janet Forstner, senior

scientist in Structural Biology

and Biochemistry, has received

the Allison Roach Alumna of

the Year award from Branksome

Hall in recognition of her

outstanding achievements as

a researcher and teacher.

Branksome Hall, founded in

1903, is a leading Canadian

independent school for girls.

Dr. Sergio Grinstein, head

of the Cell Biology Research

Program, and Dr. Amira Klip,

senior scientist, Cell Biology,

were named fellows of the Royal

Society of Canada by the

Canadian Academy of the

Sciences and Humanities, the

senior national body of distinguished

Canadian scientists

and scholars.

Dr. Lorelei Lingard, a

scientist-track investigator in

Population Health Sciences,

won the prestigious T. Hale Ham

Award for New Investigators.

The award, presented by the

Association of American Colleges

(AAMC), honours the highest

ranking paper written by a new

investigator.

Dr. Deborah O’Connor, senior

associate scientist in Integrative

Biology, received the Pinnacle

Award of Excellence from Ross

Products Division, Abbott

Laboratories.

Dr. Stephen Scherer, Genetics

and Genomic Biology, was named

one of Canada’s Top 40 under 40.

The award recognizes the

achievements of 40 of this

country’s brightest young individuals,

and was announced in

the May 2000 issue of Report

on Business Magazine.

Dr. Bonnie Stevens won the

Young Investigator Award in

Pediatric Pain sponsored by

AstraZeneca for her scholarly

scientific contributions to

advancing the understanding

of pain in infants and children.

Dr. Lap-Chee Tsui, HSC’s

geneticist-in-chief, was named

to the Order of Ontario.

The Order of Ontario is the

province’s highest and most

prestigious honour and recognizes

those who have enriched

the lives of others by attaining

the highest standards of

excellence and achievement

in their respective fields.

Dr. Lu-Yang Wang, Brain and

Behaviour Research, was recently

awarded an EJLB Foundation

Research Scholar Award. This

award is one of the most

prestigious awards for young

neuroscience investigators.

Dr. Wang was one of six successful

recipients from a large number

of international researchers.

Dr. Wang was also selected as

one of six recipients of the 2001

Burroughs Wellcome Fund New

Investigator Award in Basic

Pharmacological Sciences. Wang

was chosen as the University of

Toronto’s candidate to compete

for this North American award,

and he was the only successful

applicant from Canada.

Research Institute Citizens

of the Year Dr. Philip Collman

of Research Computing and

Dr. Harry Schachter, emeritus

scientist in Structural Biology

and Biochemistry, were named

Citizens of the Year. The annual

award is given to research staff

members who consistently

“go above and beyond” expectations

in carrying out their work.

Candidates are nominated by

their co-workers and chosen

by a committee of past award

winners. The awards were presented

at the 13th annual

Research Institute scientific

retreat in November 2000.

External leadership

appointments

Dr. Roderick McInnes, holder of

the Anne and Max Tanenbaum

Chair in Molecular Medicine at

The Hospital for Sick Children,

was appointed the inaugural

scientific director of the Institute

of Genetics of the Canadian

Institutes of Health Research

(CIHR). The scientific directors,

appointed to a four-year term,

are charged with building

national research initiatives in

their area of research, creating

strategic partnerships with the

public, private and voluntary

sectors, and fostering the translation

of research into improved

health. Scientific directors

manage their institute from

where they currently conduct

their own research.

Three HSC researchers were

also named to the CIHR

Institute Advisory Boards. Each

of the 13 CIHR institutes has

an advisory board made up of

15 to 18 individuals chosen from

more than 1,300 nominations

from Canada and abroad.

❙ Dr. Marlene Rabinovitch,

senior scientist and head of

Cardiovascular Research and

holder of the Heart and Stroke

Foundation of Ontario/Robert

Freedom Chair in Cardiovascular

Science, has been

named to the advisory board

for the Institute of Circulatory

and Respiratory Health.

❙ Dr. Michael Salter, senior

scientist, Brain and Behaviour

Research and director of the

University of Toronto Centre

for the Study of Pain, was

chosen to sit on the Institute

of Neurosciences, Mental

Health and Addiction’s

advisory board.

❙ Dr. Bonnie Stevens, senior

scientist, Population Health

Sciences, was named to the

advisory board of the Institute

of Human Development,

Child and Youth Health.

Internal leadership

appointments

Dr. James Wright, senior

scientist, was appointed head

of the Population Health

Sciences Research Program.

Dr. Wright is a professor of

Surgery and Health Administration

at the University

of Toronto and also holds the

Robert B. Salter Chair in

Paediatric Surgical Research

at The Hospital for Sick

Children.

Dr. Howard Lipshitz, a senior

scientist in the Research Institute

and the former associate director

of Faculty Development, was

appointed the head of the

Developmental Biology

Research Program.

New scientific

appointments to the

Research Institute

The following scientists were

appointed to the Research

Institute in 20002001:

❙ Dr. Eric Bouffet, Brain and

Behaviour Research

❙ Dr. Julie Brill, Developmental

Biology

❙ Dr. Benoit Bruneau,

Cardiovascular Research

❙ Dr. Manuel Carcao, Population

Health Sciences

❙ Dr. Anthony Chan,

Integrative Biology

❙ Dr. Yigal Dror, Infection,

Immunity, Injury and Repair

Research

❙ Dr. Colin Macarthur,

Population Health Sciences

❙ Dr. Christopher Macgowan,

Integrative Biology

❙ Dr. Michael Noseworthy,

Integrative Biology

❙ Dr. Deborah O’Connor,

Integrative Biology

❙ Dr. Anne Opavsky, Infection,

Immunity, Injury and Repair

Research

❙ Dr. Bonnie Stevens, Population

Health Sciences

❙ Dr. Chet Tailor, Infection,

Immunity, Injury and Repair

Research

Research Institute

29


Research activities

Annual Report 2000-2001

30

Mohamed Abdelhaleem, Cancer

& Blood Research: Cell death in

leukaemia and the role of helicases

in cancer

My laboratory is interested in two areas of

research, cell death and the role of helicases

in cancer. We are focusing on two types

of cell death in leukaemia, cell death in

response to established and novel therapeutic

agents, and cell death involving

death receptors. We are also studying the

role of some of the known and novel

members of the DDX family of helicases

in carcinogenesis.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Canadian

Institutes of Health Research and The Hospital

for Sick Children Foundation.

Khosrow Adeli, Structural Biology &

Biochemistry: Molecular and cellular

biology of lipoprotein metabolism

in cardiovascular disease, insulinresistance

syndrome, diabetes, and

paediatric obesity

Genetic mutations that affect hepatic lipid

metabolism in children such as familial

hypercholesterolaemia, as well as common

metabolic disorders such as obesity and

insulin resistance, are associated with

paediatric hyperlipidaemia and premature

atherosclerosis. A common finding in these

conditions is the hepatic overproduction

of apolipoprotein B (apoB) and, therefore,

increased plasma levels of atherogenic

lipoproteins. My colleagues and I are

currently investigating the regulation of

apoB gene expression in human liver cells

at posttranscriptional levels of protein

translocation and intracellular degradation.

We are studying intracellular degradative

mechanisms to identify the proteases and

the molecular chaperones involved. We

are also exploring the mechanisms that

mediate overproduction of apoB in insulin

resistance, diabetes, and childhood obesity

at the cellular and molecular levels.

Taghibiglou C, Carpentier A, Rudy D, Aiton A,

Lewis G, Adeli K. Mechanisms of hepatic very low

density lipoprotein overproduction in insulin

resistance: evidence for enhanced lipoprotein assembly,

reduced intracellular ApoB degradation and increased

microsomal triglyceride transfer protein in a fructosefed

hamster model. J Biol Chem 2000;275:8416-8425.

Cavallo D, Rudy D, Mohammadi A, Macri J, Adeli

K. Studies on degradative mechanisms mediating

post-translational fragmentation of apolipoprotein B

and the generation of the 70-kDa fragment. J Biol

Chem 1999;274:23135-23143.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Heart and

Stroke Foundation of Ontario, Natural Sciences

and Engineering Research Council of Canada, and

SmithKline Beecham Pharma.

Upton Allen, Population Health

Sciences: Infections in

immunocompromised children

My research focuses on infections in

children with weakened immune systems.

These children include organ-transplant

recipients and those with human immunodeficiency

virus (HIV) infection. I have

spearheaded national studies on zidovudine

resistance among children with HIV and,

in 1999, led a group of investigators in the

first multicentred drug trial for children

with HIV in Canada. My research also

investigates herpes-group infections found

in organ-transplant recipients and examines

the role of cytokines in immunosuppressed

patients. Studies include an examination of

the role of Epstein-Barr virus (EBV)-load

measurements in the early diagnosis of

posttransplant lymphoproliferative disease

(PTLD), prevention of EBV diseases after

transplantation, a survey of PTLD in

Canadian paediatric transplant recipients,

risk factors for PTLD in paediatric transplant

recipients, among others

Allen UD, Hebert D, Moore D, Dror Y, Wasfy S,

the Canadian PTLD Survey Group-1998.

Epstein-Barr virus-related post-transplant

lymphoproliferative disease in solid organ transplant

recipients, 1988-97: A Canadian multi-centre

experience. Pediatr Transplant 2001;5:1-8.

Allen U, Hebert D, Tran D, Petric M, Tellier R,

Taylor G, Stephens D, West L, Superina R, Dosch H,

Wasfy S, Nelson S. The utility of semiquantitative

polymerase chain reaction (PCR) for Epstein-Barr

virus among pediatric solid organ transplant

recipients with and without post-transplant

lymphoproliferative disease (PTLD). Clin Infect

Dis 1999;29:1058.

Appointed to the Department of Paediatrics at

the University of Toronto. External support

provided by Abbott Laboratories Limited, Exergen

Corporation, Fujisawa Healthcare, Inc., Genesis

Biopharmaceuticals/Medimmune, Merck Frosst

Canada & Co., Pfizer Canada Inc., The Hospital for

Sick Children Foundation, The Liposome Company,

Inc., and Children’s Hospital of Eastern Ontario.

Benjamin Alman, Developmental

Biology: Developmental pathways in

musculoskeletal neoplasia and fibrosis

My laboratory studies the molecular

mechanisms responsible for the deregulation

of cellular growth control in musculoskeletal

neoplasia. We particularly focus on

aggressive fibromatosis (desmoid tumour)

and cartilage neoplasia (e.g. enchondromatosis

and chondrosarcoma), both of

which are difficult to treat with current

therapies. We identified developmental

signalling pathways that are inappropriately

activated in both types of lesions. Our

current work involves determining

mutations that are responsible for the

dysregulation of the pathways, identifying

novel mediators in the pathways,

developing animal models based

on pathway activation, and determining

whether a pharmacologic approach can be

used to modulate pathway activation. This

will ultimately identify novel treatments for

these tumours. Some of the information

learned from aggressive fibromatosis can

be applied to other fibrotic processes

(e.g., hypertrophic scar), and we are

working to determine whether the same

pathways are activated in these processes.

Tejpar S, Nollet F, Li C, Wunder JS, Michils G,

dal Cin P, Van Cutsem E, Bapat B, van Roy F,

Cassiman JJ, Alman BA. Predominance of betacatenin

mutations and beta-catenin dysregulation in

sporadic aggressive fibromatosis (desmoid tumor).

Oncogene 1999;18:6615-6620.

Poon R, Smits R, Li C, Jagmohan-Changur S,

Kong M, Cheon S, Yu C, Fodde R, Alman BA.

Cyclooxygenase-two (COX-2) modulates

proliferation in aggressive fibromatosis (desmoid

tumor). Oncogene 2001;20:451-460.

Holder of a Tier II Canada Research Chair.

Appointed to the Department of Surgery at the

University of Toronto. External support provided by

Biorthex Inc., Canadian Institutes of Health

Research, National Cancer Institute of Canada, and

Orthopaedic Research and Education Foundation.

Maureen Andrew, Population Health

Sciences: Blood clotting disorders

during infancy and childhood

My research has focused on understanding

the blood clotting system in healthy infants

and children, as well as in children with

a variety of serious diseases such as cancer,

congenital heart disease, and prematurity.

Blood clots in small and large vessels can

damage organ function, resulting in serious

secondary illnesses that may be as serious

as the primary disease. Using a combination

of laboratory experiments, animal models,

and clinical studies of children, my

colleagues and I are learning how to prevent

blood clots and treat them more effectively.

Monagle P, Adams M, Mahoney M, Ali K,

Barnard D, Bernstein M, Brisson L, David M,

Desai S, Scully MF, Halton J, Israels S, Jardine L,

Leaker M, McCusker P, Silva M, Wu J, Anderson R,

Andrew M, Massicotte MP. Outcome of pediatric

thromboembolic disease: a report from the

Canadian Childhood Thrombophilia Registry.

Pediatr Res 2000;47:763-766.

Marzinotto V, Monagle P, Chan A, Adams M,

Massicotte P, Leaker M, Andrew M. Capillary whole

blood monitoring of oral anticoagulants in children

in outpatient clinics and the home setting. Pediatr

Cardiol 2000;21:347-352.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Avocet Medical Inc., Bloorview Childrens Hospital

Foundation, Canadian Institutes of Health

Research, Heart and Stroke Foundation of Ontario,

Knoll Pharma Inc., and Leo Pharma Inc.

Beverley Antle, Population Health

Sciences: Social support, self-esteem,

and successful transitions for young

people with chronic health conditions

Children with chronic health conditions

and physical disabilities have more

difficulties in social relationships and

in later transitions to independent lives

than their peers. Self-esteem and social

support are two factors that appear to play

a key protective role. My multiyear

interdisciplinary program of research

focuses on understanding the factors that

contribute to social adjustment, especially

the role of social support in promoting selfesteem

and successful transition. This year

I conducted studies that examine the

role of parents in supporting their

children and that test an approach to

transition education and planning for

young people and their parents.

Antle BJ, Wells LM, Goldie Salter R, DeMatteo D,

King SM. The challenges of parenting for families

living with HIV/AIDS. Social Work 2001;46:

159-169.

Appointed to the Faculty of Social Work at the

University of Toronto. External support provided

by Bayer Institute for Health Care Communication,

Bloorview Childrens Hospital Foundation, Garrod

Association, Social Sciences and Humanities

Research Council, and Spina Bifida and

Hydrocephalus Association of Canada.

Research Institute

31


Research activities

Annual Report 2000-2001

32

Darius Bägli, Infection, Immunity,

Injury & Repair: Cell-extracellular

matrix interactions in urinary bladder

disease

Using the bladder as a dynamic model

system, I primarily study the cell-matrix

interactions governing fibroproliferative

disease. My colleagues and I are investigating

the role of a novel hyaluronic acid-binding

protein, RHAMM (CD168), which

regulates proliferation, motility, and

extracellular matrix (ECM) remodelling in

a wide variety of epithelial and mesenchymal

cells. The gene expression of

RHAMM and structural matrix proteins,

such as collagen, is sensitive to the type

of mechanical strain delivered. Interfering

with RHAMM function modulates both

gene responses and cell contraction.

Furthermore, the smooth-muscle cells’

ability to remodel the ECM seems

balanced with its ability to regulate

smooth-muscle-cell behaviour. We recently

discovered a potential role for MAP kinase

in these processes. Ultimately, we wish

to exploit these mechanisms to treat

fibroproliferative disease.

Bägli DJ, Joyner BD, Mahoney SR, McMulloch L.

The hyaluronic acid receptor is induced by stretch

injury of the rat bladder in vivo and influences

smooth muscle cell contraction in vitro. J Urol

1999;162:832-840.

Savani RC, Bägli DJ, Harrison RE, Turley EA.

The role of hyaluronan/receptor interactions in

wound repair. In: Garg H, Longaker MT, editors.

Scarless wound healing. New York: Marcel Dekker;

2000. p. 115-142.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Materials and Manufacturing Ontario and The

Physicians’ Services Incorporated Foundation.

Marcia Barnes, Brain & Behaviour

Research: Cognitive and academic

outcome in children with congenital

and acquired brain injuries

My research program investigates the

cognitive and neurobiological origins

of academic difficulties experienced by

children with different types of brain injury.

We study reading comprehension and

arithmetic processing in school-aged

children with spina bifida and in children

with traumatic head injury. Another project

focuses on the development of early literacy

and number skills in preschoolers with

spina bifida. A new multisite project will

follow children who sustain accidental

and nonaccidental head injuries at a very

young age, examining the development

of cognitive and social outcomes, and early

literacy and number skills. We are also

part of a cross-Canada clinical trial of

moderate hypothermia for severe paediatric

head injury that uses neuropsychological

outcomes.

Barnes MA, Dennis M, Wilkinson M. Reading after

closed head injury in childhood: effects on decoding,

fluency, and comprehension. Dev Neuropsychol

1999;15:1-24.

Barnes MA, Faulkner H, Dennis M. Poor reading

comprehension despite fast word decoding in children

with hydrocephalus. Brain Lang 2001;76:35-44.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Canadian Institutes of Health Research, National

Institutes of Health, and Ontario Neurotrauma

Foundation.

Cathy Barr, Brain & Behaviour

Research: The genetics of neuropsychiatric

disorders and behaviour

The focus of my research is the genetics

of psychiatric and neurological disorders

for which a genetic predisposition has been

established, for example, attention-deficit

hyperactivity disorder, childhood-onset

anxiety disorders, childhood-onset

depression, reading disabilities, and

Tourette syndrome. Numerous studies

have implicated an imbalance in the

neurotransmitter systems or neurological

development for these disorders. My

colleagues and I are able to test specific

candidate genes from these systems by

screening these genes for DNA changes

that may contribute to the genetic

predisposition to neuropsychiatric disorders.

Barr CL, Feng Y, Wigg K, Bloom S, Roberts W,

Malone M, Schachar R, Tannock R, Kennedy JL.

Identification of DNA variants in the SNAP-25

gene and linkage study of these polymorphisms and

attention-deficit hyperactivity disorder. Mol

Psychiatry 2000;5:405-409.

Barr CL, Wigg KG, Pakstis AJ, Kurlan R, Pauls D,

Kidd KK, Tsui L-C, Sandor P. Genome scan for

linkage to Gilles de la Tourette syndrome. Am J Med

Genet 1999;88:437-445.

Appointed to the Department of Psychiatry at the

University of Toronto. External support provided

by Canadian Institutes of Health Research,

National Institutes of Health, and Psychiatry

Endowment Fund.

Maru Barrera, Population Health

Sciences: Psychological adjustment,

quality of life, and coping with

paediatric cancer and its treatment

I have continued to explore the

psychological effects of bone marrow

transplantation on the ill child and family,

and the progression of parental bereavement.

Outcome research is ongoing on

procedural pain management and the

effectiveness of manualized group therapy

for enhancing coping strategies in siblings

of children with cancer. Three new projects

have been funded: social skills training for

survivors of paediatric brain tumours,

assessment of health-related quality of life

of paediatric bone cancer survivors, and an

intervention for children with cancer that

uses a children’s story. I have continued

collaborating with other researchers to

study the neurocognitive effects of in utero

exposure to organic solvents and the late

effects of paediatric cancer, a national

project sponsored by Health Canada.

Barrera M. Brief clinical report: procedural pain

and anxiety management with mother and sibling as

co-therapists. J Pediatr Psychol 2000;25:117-121.

Barrera M, Boyd-Pringle L, Sumbler K, Saunders F.

Quality of life and behavioral adjustment after

pediatric bone marrow transplantation. J Bone

Marrow Transplant 2000;26:427-435.

Appointed to the Departments of Community

Health, Public Health Sciences, Human Development

and Applied Psychology, and the Institute of

Medical Science at the University of Toronto.

External support provided by Brainchild, National

Cancer Institute of Canada, Elizabeth Lue Bone

Marrow Foundation, and Sociobehavioural Cancer

Research Centre Pilot Fund.

Sylvain Baruchel, Population Health

Sciences: New agent and innovative

therapies program in paediatric

oncology

The objective of the new agent and

innovative therapy (NAIT) program in

paediatric oncology, of which I am the

director, is to develop clinical trials for

drugs or biological agents (e.g., chemotherapy,

immunotherapy, radioisotopes,

anti-angiogenesis) that are more effective

and less toxic than current therapies, and

that protect children from the complications

of chemotherapy. This unique

interdisciplinary program brings together

professionals from oncology, clinical

pharmacology, psychology, bioethics,

nursing, and pharmacy. The NAIT

program focuses on expanding the number

of agents that are available for phase 1

trials. In this program, my colleagues and

I also carry out ground-breaking research

that assesses the ethical aspects and the

impact of these treatments on the quality

of life. We have recently published a lead

article opening a new field of research

combining low-dose chemotherapy and

anti-angiogenic therapy.

Loebstein R, Atanackovic G, Bishai R, Wolpin J,

Khattak S, Hashemi G, Gobrial M, Baruchel S,

Ito S, Koren G. Risk factors for long-term outcome

of ifosfamide-induced nephrotoxicity in children.

J Clin Pharmacol 1999;39:454-461.

Klement G, Baruchel S, Rak J, Man S, Clark K,

Hicklin DJ, Bohlen P, Kerbel RS. Continuous lowdose

therapy with vinblastine and VEGF receptor-2

antibody induces sustained tumor regression without

overt toxicity. J Clin Invest 2000;105:1-11.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Brainchild, Cytogen Corporation, Institut de

Recherches Internationales Servier, Issho Genki

International Limited, National Institutes of

Health, Paediatric Consultants, Pharmacia Canada

Inc., and Schering Canada Inc.

Christine Bear, Structural Biology &

Biochemistry: Chloride channels

and their role in cell physiology and

pathophysiology

For cystic fibrosis and Dent disease,

mutations in genes that code for the

chloride channels CFTR and ClC-5,

respectively, cause disease. Both of these

chloride channels act in epithelial tissue,

a tissue that forms a semipermeable barrier

between the body and the environment.

Since maintenance of normal epithelial-cell

function is important for health, the overall

goal of my laboratory is to understand how

the chloride channels CFTR and ClC-5

normally contribute to the function of

epithelial tissue and, further, how mutant

versions of these channels that are known

to exist in patients, can cause disease.

Our diverse experimental approaches to

these questions include biochemical and

biophysical studies of purified chloride

channels, electrical recordings from single

cells, and in vivo and in vitro studies of

animal models of disease.

Kogan I, Ramjeesingh M, Huan LJ, Wang Y,

Bear CE. Perturbation of the pore of the cystic

fibrosis transmembrane conductance regulator

(CFTR) inhibits its ATPase activity. J Biol Chem

2001;276:11575-11581.

Ramjeesingh M, Li C, Huan LJ, Garami E, Wang Y,

Bear, CE. Quaternary structure of the chloride

channel ClC-2. Biochemistry 2000;39:13838-13847.

Appointed to the Department of Physiology at the

University of Toronto. External support provided

by Canadian Cystic Fibrosis Foundation, Canadian

Institutes of Health Research, and National

Institutes of Health.

Research Institute

33


Research activities

Annual Report 2000-2001

34

Laurence Becker, Brain & Behaviour

Research: The role of the cytoskeleton

in proliferation, differentiation,

and invasiveness of astrocytomas

My interest is in the structural and

molecular aspects of brain tumours.

Astrocytomas are characterized by

glial fibrillary acidic protein (GFAP)

intermediate filaments, which form a

structural link between the nucleus and

the plasma membrane. The observation

of reduced intermediate filaments in

anaplastic astrocytomas has led to

experimental perturbations of GFAP,

showing that it plays a key role in the

dynamic interaction of microfilaments,

CD44, integrin receptors, and the

extracellular matrix. GFAP links to actin

and to the cytoplasmic domains of integrin

by means of well-characterized actinbinding

proteins. We have shown that

modulation of GFAP expression affects

astrocytoma differentiation, growth, and

invasiveness. The mechanism by which

GFAP produces these complex cellular

rearrangements and signalling cascades

is the focus of current studies.

Jung S, Ackerley C, Ivanchuk S, Mondal S,

Becker LE, Rutka J. Tracking the invasiveness of

human astrocytoma cells by using green fluorescent

protein in an organotypical brain slice model.

J Neurosurg 2001;94:80-89.

Rutka JT, Muller M, Hubbard SL, Forsdike J,

Dirks PB, Jung S, Tsugu A, Ivanchuk S, Costello P,

Mondal S, Ackerley C, Becker LE. Astrocytoma

adhesion to extracellular matrix: functional

significance of integrin and focal adhesion kinase

expression. J Neuropathol Exp Neurol 1999;58:

198-209.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, and Paediactrics at

the University of Toronto. External support

provided by Canadian Institutes of Health Research.

Joseph Beitchman, Brain &

Behaviour Research: 1) Long-term

outcome of speech and language

disorders; 2) Aggressive behaviour

and possible genetic factors

1) Using data collected as part of the

Ottawa Language Study, my colleagues and

I are exploring the outcomes of childhood

speech and language disorders in young

adults. Our results so far point to the longterm

durability of speech and language

problems; they also suggest that early

speech and language problems increase

the risk of psychiatric problems in young

adults, especially anxiety disorders, and

of behavioural problems in boys. 2) We are

also conducting a study to examine the

relation between certain genetic factors

and problems with aggressive behaviour.

The level and type of aggressive behaviour

are assessed with questionnaires and a

computer game. Results are suggestive,

but our sample is, as yet, too small to draw

firm conclusions about the relation between

genetic factors and the tendency to

aggressive behaviour.

Beitchman JH, Douglas L, Wilson B, Johnson C,

Young A, Atkinson L, Escobar M, Taback N.

Adolescent substance use disorders: findings from

a 14-year follow-up of speech/language-impaired

and control children. J Clin Child Psychol

1999;28:312-321.

Johnson CJ, Taback N, Escobar M, Wilson B,

Beitchman JH. Local norming of the Test of

Adolescent/Adult Language-3 in the Ottawa Speech

and Language Study. J Speech Lang Hear Res

1999;42:761-766.

Holder of the TD Bank Financial Group Chair in

Child and Adolescent Psychiatry at The Hospital

for Sick Children. Appointed to the Department of

Psychiatry at the University of Toronto. External

support provided by The Hospital for Sick Children

Foundation.

Diane Benoit, Population Health

Sciences: Parent-infant attachment

and common problems in infancy

My research activities focus on infants’

attachment relationships with their parents,

the identification of parents’ atypical

behaviours associated with insecure or

disorganized infant attachment, and

interventions to improve parent-infant

relationship difficulties. My research team

and I are currently involved in three

studies. One examines parents’ specific

behaviours associated with a type of

attachment that relates to later serious

emotional and behavioural problems.

The second focuses on the development

of an instrument to assess caregivers’ ability

to recognize infant emotion. The third

relates to the development of a screening

questionnaire to assess psychiatric problems

in infants, including regulation disorder.

Benoit D, Wang EE, Zlotkin SH. Discontinuation

of enterostomy tube feeding by behavioral treatment

in early childhood: a randomized controlled trial.

J Pediatr 2000;137:498-503.

Coolbear J, Benoit D. Failure to thrive: risk for

clinical disturbance of attachment? Infant Ment

Health J 1999;20:87-104.

Appointed to the Department of Psychiatry at the

University of Toronto. External support provided by

Ontario Mental Health Foundation and Psychiatry

Endowment Fund.

Victor Blanchette, Population Health

Sciences: Congenital and acquired

bleeding disorders

I study children with congenital and

acquired bleeding disorders, including

childhood immune thrombocytopenic

purpura (ITP), haemophilia, and von

Willebrand disease. As part of the

Canadian Children’s Platelet Study

Group, I am developing a disease-specific

health-related quality-of-life instrument for

patients with ITP and studying the

mechanisms of action of anti-D. In

collaboration with Drs Margaret Rand and

Manuel Carcao, I have successfully used an

automated platelet-function analyzer to

screen children for von Willebrand disease

and clinically significant congenital platelet

disorders. This test may effectively replace

the invasive and unreliable skin bleedingtime.

In a Canadian prospective doseescalation

study of factor VIII prophylaxis,

my research team’s aim is to determine the

optimal factor-replacement strategy to

prevent recurrent joint bleeding and

haemophilic arthropathy in young boys

with severe haemophilia A.

Dror Y, Blanchette VS. Essential thrombocythaemia

in children. Br J Haematol 1999;107:691-698.

Blanchette V, Carcao M. Approach to the

investigation and management of immune

thrombocytopenic purpura in children. Semin

Hematol 2000;37:299-314.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Bayer Inc., Canadian Institutes of Health

Research, Cangene Corporation, Dade Behring Inc.,

Heart and Stroke Foundation of Ontario, National

Institutes of Health, and The Hospital for Sick

Children Foundation.

Joan Boggs, Structural Biology &

Biochemistry: Membrane structure

and function

My research program is aimed at

understanding the structural mechanisms

of cell-membrane behaviour, particularly

in myelin and the oligodendrocyte. My

colleagues and I are currently focusing on

the roles of myelin proteins in interactions

with the cytoskeleton and the role of

glycosphingolipids in cell-surface

phenomena. We also study the interactions

of other proteins and peptides with the

lipid bilayer using a number of biochemical

and biophysical techniques, such as

hydrophobic photolabelling, electron

paramagnetic resonance spectroscopy (spin

labelling), and Fourier-transform infrared

spectroscopy. These are excellent techniques

for studying membrane proteins and lipids.

We expect that these studies will aid in the

development of treatments for diseases in

which the membrane constituents are

abnormal and in the development of

drugs that act on membranes.

Boggs JM, Menikh A, Rangaraj G. Trans interaction

between galactosylceramide and cerebroside sulfate

across apposed bilayers. Biophys J 2000;78:874-885.

Boggs JM, Rangaraj G. Interaction of lipid-bound

myelin basic protein with actin filaments and

calmodulin. Biochemistry 2000;39:7799-7806.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, and Immunology at

the University of Toronto. External support

provided by Canadian Institutes of Health Research

and Multiple Sclerosis Society of Canada.

Desmond Bohn, Population Health

Sciences: Clinical factors affecting

and modifying brain injury

My principal area of interest in the past

year has been salt and water homeostasis

and brain injury. In collaboration with

Dr. Mitchell Halperin from St. Michael’s

Hospital, my colleagues and I have been

conducting prospective and retrospective

studies on the administration of

intravenous fluid and abnormalities in

salt and water homeostasis in hospitalized

children which results in cerebral oedema.

This is due to oversecretion of vasopressin.

In addition, the multicentre Canadian

randomized trial of hypothermia in

traumatic brain injury continues to enrol

patients. This trial studies the effect of

cooling on long-term outcomes, as

determined from cognitive and

intellectual function.

Halberthal M, Halperin ML, Bohn D. Lesson of the

week: Acute hyponatraemia in children admitted to

hospital: retrospective analysis of factors contributing

to its development and resolution. BMJ

2001;322:780-782.

Porzio P, Halberthal M, Bohn D, Halperin ML.

Treatment of acute hyponatremia: ensuring the

excretion of a predictable amount of electrolyte-free

water. Crit Care Med 2000;28:1905-1910.

Appointed to the Departments of Anaesthesia and

Paediatrics at the University of Toronto. External

support provided by Bayer Inc. and The Hospital

for Sick Children Foundation.

Research Institute

35


Research activities

Annual Report 2000-2001

36

Gabrielle Boulianne, Developmental

Biology: Genetic and molecular

analysis of neural development,

function, and disease

My colleagues and I are interested in

understanding how cell fate is determined

during neuronal development in Drosophila.

In recent years, we have focused on a group

of genes called neurogenic genes that interact

in a common pathway to determine the

fate of virtually every cell type in many

complex organisms. In a second area of

research, we are investigating the molecular

basis of neurotransmitter release. Using

genetic and molecular approaches, we have

identified and characterized the function

of the NSF gene that plays a central role in

this process. Finally, we are also developing

Drosophila models of aging and neurodegenerative

disease. This work involves

the analysis of SOD and presenilins for

which mutations have been implicated in

amyotrophic lateral sclerosis and Alzheimer

disease, respectively.

Yeh E, Zhou L, Rudzik N, Boulianne GL.

Neuralized functions cell autonomously to regulate

Drosophila sense organ development. EMBO J

2000;19:4827-4837.

Stewart BA, Mohtashami M, Trimble WS,

Boulianne GL. SNARE proteins contribute to

calcium cooperativity of synaptic transmission.

Proc Natl Acad Sci U S A 2000;97:13955-13960.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Alzheimer’s

Association, American Health Assistance

Foundation, Canadian Institutes of Health

Research, Natural Sciences and Engineering

Research Council of Canada, and Novartis

Pharmaceuticals Canada Inc.

Katherine Boydell, Population

Health Sciences: Children’s health

and mental health systems research

My interests are in using both quantitative

and qualitative methods to explore access,

service delivery, and outcomes in the

children’s health and mental health system.

My colleagues and I are currently involved

in a follow-up study that examines the

outcomes of youth eligible for admission to

a psychiatric crisis unit, the implementation

of a child- and adolescent-functioning

assessment tool in the community, and

an evaluation of a parenting alliance

between The Hospital for Sick Children

and 26 community agencies. We also have

a 5-year grant to examine the impact of

membership in a family self-help group

at both the individual and systems level.

We have funding to study motivation in

youth who have experienced psychosis

and youth who are homeless. We are also

designing an infrastructure for research

communication and dissemination to

measure outcomes for children’s mental

health. We have strong links to and pursue

collaborative research with community

health care professionals.

Morrell-Bellai TL, Goering P, Boydell KM.

Becoming and remaining homeless: a qualitative

investigation. Ment Health Nurs 2000;21:581-604.

Boydell KM, Goering P, Morrell-Bellai T. Narratives

of identity: re-presentation of self in people who

are homeless. Qual Health Res 2000;10:26-38.

Appointed to the Departments of Psychiatry

and Public Health Sciences at the University of

Toronto. External support provided by Ministry of

Health and Long-Term Care, Ontario Mental Health

Foundation, and The Hospital for Sick Children

Foundation.

Julie Brill, Developmental Biology:

Molecular mechanisms and

developmental control of cytokinesis

The development and propagation of living

organisms relies on cytokinesis, the splitting

of one cell into two. A remarkable variation

of this universal process occurs during

germ-cell differentiation: instead

of separating, cells remain connected by

intercellular bridges called ring canals.

To determine how ring canals form during

spermatogenesis, I identified the genes

required for this process in the fruit fly

Drosophila melanogaster. I showed that fwd,

one of these genes, encodes a lipid kinase

implicated in regulating both the actin

cytoskeleton and secretion, processes

important in cell division. My laboratory

is investigating the participation of fwd in

ring-canal assembly by identifying targets

of fwd regulation and proteins that interact

with the fwd gene product to produce

normal sperm.

Brill JA, Hime GR, Scharer-Schuksz M, Fuller MT.

A phospholipid kinase regulates actin organization

and intercellular bridge formation during germline

cytokinesis. Development 2000;127:3855-3864.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

Benoit Bruneau, Cardiovascular

Research: Molecular genetics of

heart formation

My research interests lie in the genetic and

molecular basis of the formation of the

mammalian heart. More specifically, I am

interested in finding out how cardiac

transcription factors regulate other genes

during embryogenesis and how a disruption

of these processes can lead to congenital

heart defects. I am using the mouse as a

genetically modifiable organism to

investigate these questions. Two families

of genes, the Iroquois and T-box family

of transcription factors, are the current

focus of my work. My colleagues and

I have shown that they play important roles

in distinct aspects of heart development

and disease. Current research involves

further dissection of the genetic and

morphological pathways that are regulated

by these transcription factors.

Bruneau BG, Bao ZZ, Fatkin D, Xavier-Neto J,

Georgakopoulos D, Maguire CT, Berul CI, Kass DA,

Kuroski-de Bold ML, de Bold AJ, Conner DA,

Rosenthal N, Cepko CL, Seidman CE, Seidman JG.

Cardiomyopathy in Irx4-deficient mice is preceded by

abnormal ventricular gene expression. Mol Cell Biol

2001;21:1730-1736.

Bruneau BG, Logan M, Davis N, Levi T, Tabin CJ,

Seidman JG, Seidman CE. Chamber-specific cardiac

expression of Tbx5 and heart defects in Holt-Oram

syndrome. Dev Biol 1999;211:100-108.

Appointed to the Departments of Molecular and

Medical Genetics, and Paediatrics at the University

of Toronto.

Manuel Buchwald, Genetics

& Genomic Biology: Studies of

the fundamental defect in

Fanconi anaemia

My laboratory works on a genetic condition

called Fanconi anaemia, which causes

congenital malformations and predisposes

patients to a high incidence of leukaemia.

This disorder is, therefore, a model for

the study of the factors that cause these

abnormalities. Our goal is to understand

this disease so that novel treatments,

including gene therapy, become feasible.

We have been determining the roles of

the genes defective in seven distinct sets

of patients in the causation of the cancer

and the malformations. We have isolated

five of these genes (FANCA, FANCC,

FANCE, FANCF and FANCG). Our

current projects involve the analysis of the

role of the Fanconi anaemia proteins in

normal function and the effect of their

absence on the generation of disease.

de Winter JP, Léveillé F, van Berkel CGM,

Rooimans MA, van der Weel L, Steltenpool J,

Demuth I, Morgan NV, Alon N, Bosnoyan-Collins

L, Lightfoot J, Leegwater PA, Waisfisz Q, Komatsu

K, Arwert F, Pronk JC, Mathew CG, Digweed M,

Buchwald M, Joenje H. Isolation of a cDNA

representing the Fanconi anemia complementation

group E gene. Am J Hum Genet 2000;67:

1306-1308.

Wong JCY, Alon N, Norga K, Kruyt FAE,

Youssoufian H, Buchwald M. Cloning and analysis

of the mouse Fanconi anemia group A cDNA and

an overlapping penta zinc finger cDNA. Genomics

2000;67:273-283.

Holder of the Lombard Insurance Chair in Paediatric

Research at The Hospital for Sick Children.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, National Cancer Institute

of Canada, and The Hospital for Sick Children

Foundation.

Lori Burrows, Infection, Immunity,

Injury & Repair Research: Genetics

of bacterial biofilms and development

of biofilm-resistant medical devices

One of the critical limitations of common

medical devices such as urinary catheters

and intravenous lines is bacterial and fungal

infection. These devices provide a pathway

by which pathogens may enter the body.

In addition, microorganisms that attach

to surfaces differentiate to form complex

multicellular structures called biofilms that

are extremely resistant to most classes of

antibiotics. In my laboratory, we study

the genetic mechanisms that lead to the

differentiation of bacteria into antibioticresistant

biofilms to better understand how

we could circumvent this very common

problem. Another area of interest is the

dissection of the specific cell-surface

characteristics (lipopolysaccharide, flagella,

and pili) that allow bacteria to adhere to

various surfaces. For prevention of biofilm

formation, we are developing antimicrobial

coatings for medical devices that slowly

release antibiotics or disinfectants for

sustained periods, killing microorganisms

before they can colonize a surface.

Burrows LL, Khoury AE. Issues surrounding the

prevention and management of device-related

infections. World J Urol 1999;17:402-409.

Walsh AG, Matewish MJ, Burrows LL, Monteiro

MA, Perry MB, Lam JS. Lipopolysaccharide core

phosphates are required for viability and intrinsic

drug resistance in Pseudomonas aeruginosa.

Mol Microbiol 2000;35:718-727.

Appointed to the Department of Surgery at

the University of Toronto.

Research Institute

37


Research activities

Annual Report 2000-2001

38

John Callahan, Structural Biology

& Biochemistry: Pathophysiological

basis of lysosomal storage diseases

My laboratory is using proteomic

approaches (2D IEF/SDS-PAGE and

mass spectrometry) to characterize the

proteins of the lysosomal membrane in an

attempt to define the basis for a number of

lysosomal diseases associated with defects

in membrane transport and intracellular

signalling. To date we have identified

50 proteins, about 10 of which are novel.

Now, in collaboration with Dr. Don

Mahuran, this project has been expanded

to include other organelles such as

peroxisomes. Of longstanding interest

is the characterization of β-galactosidase

affected in the two storage diseases

GM1-gangliosidosis and Morquio disease,

type B, as a basis for devising strategies for

enzyme replacement.

Hinek A, Zhang S, Smith AC, Callahan JW.

Impaired elastic-fiber assembly by fibroblasts from

patients with either Morquio B disease or infantile

GM1-gangliosidosis is linked to deficiency in

the 67-kDa spliced variant of β-galactosidase.

Am J Hum Genet 2000;67:23-36.

Zhang S, Bagshaw R, Hilson W, Oho Y, Hinek A,

Clarke JTR, Hinek A, Callahan J W. Characterization

of β-galactosidase mutations Asp332>Asn

and Arg148>Ser, and a polymorphism, Ser532>Gly,

in a case of GM1 gangliosidosis. Biochem J

2000;348:621-632.

Appointed to the Departments of Biochemistry

and Paediatrics at the University of Toronto.

External support provided by Canadian Institutes of

Health Research.

John Chamberlain, Infection,

Immunity, Injury & Repair Research:

Immunogenetic mechanisms of

T-lymphocyte development and

function in health and disease

A major area of research in my laboratory

stems from the need for in vivo models

for studying immune function in human

disease. Our approach is to humanize

specific components (i.e., the major

histocompatibility complex molecules and

T cells) of the mouse’s immune system.

Our results that demonstrate HLA-specific

T-cell responses indicate that these systems

will provide new approaches for developing

treatments for infectious disease (e.g.,

HIV-1), autoimmunity, and graft rejection.

A second area of research is aimed at

understanding the regulation of expression

of coreceptors CD8 and CD4 during T-cell

maturation. The results of these studies

will tell us a great deal about the molecular

mechanisms controlling immune system

development, as well as about similar

problems in other differentiating systems.

Borenstein S, Graham J, Zhang XL,

Chamberlain JW. CD8+ T cells are necessary

for recognition of allelic, but not locus-mismatched

or xeno-, HLA class I transplantation antigens.

J Immunol 2000;165:2341-2353.

Dela Cruz CS, Chamberlain JW, MacDonald KS,

Barber BH. Xenogeneic and allogeneic anti-MHC

immune responses induced by plasmid DNA

immunization. Vaccine 1999;17:2479-2492.

Appointed to the Department of Immunology

and the Institute of Medical Science at the

University of Toronto. External support provided

by Canadian Institutes of Health Research,

Ministry of Health and Long-Term Care, and

Ontario HIV Treatment Network.

Helen Chan, Cancer & Blood

Research: Reversal of multidrug

resistance in retinoblastoma

Dr. Brenda Gallie and I coordinate a

multicentre randomized clinical trial that

will provide a unique opportunity to clarify

the role of cyclosporine in counteracting

multidrug resistance during chemotherapy

for retinoblastoma. This trial will also allow

me to examine the effect of multidrugresistance

proteins on tumour-progression

factors in retinoblastoma at the single-cell

level to better determine why some

retinoblastomas do not respond to therapy.

These studies will further my overall goal

to determine the most important causes of

treatment failure and tumour progression,

to target novel therapies that prevent

blindness and morbidity, and to improve

the cure rate of paediatric cancers.

Appointed to the Department of Paediatrics

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, National Cancer Institute of Canada,

and Paediatric Consultants.

Joe Clarke, Population Health

Sciences: Studies on the treatment

of lysosomal storage diseases

For many years, I have pursued formal

studies on various aspects of lysosomal

storage diseases, particularly Fabry disease,

Hunter disease, Gaucher disease, and

Tay-Sachs disease. The emphasis of my

work has shifted from basic biological

and genetic issues to matters relating

to treatment, especially by enzyme

replacement. Much of this research has

been done in collaboration with biotechnology

companies involved with the

development of products suitable for use

in enzyme-replacement therapy. During

the past year, I have played a major and

growing role in facilitating the establishment

of biotechnology industry-sponsored

clinical research programs in Nova Scotia,

British Columbia, and Ontario directed

at the evaluation of enzyme-replacement

therapy for Fabry disease (Nova Scotia and

Ontario) and mucopolysaccharideosis type

I/H (British Columbia). During the last

three years, I have also become increasingly

involved in research on health policy

decision-making related to the introduction

of new, advanced technologies for the

treatment of genetic diseases.

Smith ML, Saltzman, J, Klim P, Hanley WB,

Feigenbaum A, Clarke JTR. Neuropsychological

function in mild hyperphenylalaninemia. Am

J Ment Retard 2000;105:69-80.

Bross R, Ball RO, Clarke JTR, Pencharz PB.

Tyrosine requirements in children with classical PKU

determined by indicator amino acid oxidation. Am J

Physiol (Endocrin Metab) 2000;278: E195-E201.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

The Hospital for Sick Children Foundation.

Allan Coates, Lung Biology:

Aerosol drug delivery for children

with respiratory disease

My current work on the administration

of aerosolized drugs to the lungs of patients

with cystic fibrosis and other respiratory

disease continues and has branched out to

include the use of aerosols for the diagnosis

of asthma. Although the pharmaceutical

industry has done much research on

products that are wedded to delivery

devices, much less has been done on

nebulized agents. Moreover, some of the

scientific tools necessary to do this work

are lacking. To this end, my colleagues and

I have developed better techniques for

characterizing aerosol-droplet size, a factor

that is key to whether the droplets will

deposit in the lungs and where. Our overall

goal is to improve our understanding of

nebulization therapy for children.

Subbarao P, Brannan J, Ho B, Anderson SD,

Chan HK, Coates AL. Inhaled mannitol identifies

methacholine responsive children with active asthma.

Pediatr Pulmonol 2000;29:291-298.

Kwong WTJ, Ho SL, Coates AL. Comparison of

nebulized particle size distribution with Malvern

laser diffraction analyzer versus Andersen cascade

impactor and low-flow Marple personal cascade

impactor. J Aerosol Med 2000;13:303-314.

Appointed to the Departments of Paediatrics

and Physiology at the University of Toronto.

External support provided by Canadian Cystic

Fibrosis Foundation, Canadian Institutes of

Health Research, and Periodontix, Inc.

Amos Cohen, Infection, Immunity,

Injury & Repair Research: Molecular

mechanisms of immune deficiencies

My research over the years has been focused

on the elucidation of the mechanisms by

which mutations in genes involved in

purine metabolisms and signal transduction

cause immune-deficiency disease in children.

Using a mouse PNP knock-out as a model,

my colleagues and I are currently investigating

the molecular mechanisms by which

adenosine deaminase and purine nucleoside

phosphorylase (PNP) deficiencies cause

immunodeficiencies through the induction

of apoptosis in developing thymocytes.

The PNP knock-out mouse is also used

as a model for gene therapy. My laboratory

has a long-term interest in intrathymic

differentiation. An additional long-term

goal is elucidation of the molecular

mechanisms of childhood leukaemia.

Arpaia E, Benveniste P, Di Cristofano A, Gu Y,

Dalal I, Kelly S, Hershfield M, Pandolfi PP,

Roifman CM, Cohen A. Mitochondrial basis for

immune-deficiency: evidence from purine nucleoside

phosphorylase deficient mice. J Exp Med

2000;191:2197-2207.

Cohen A, Grunbaum E, Arpaia E, Roifman CM.

Immunodeficiency caused by purine nucleoside

phosphorylase deficiency. Immunol Allergy Clin

North Am 2000;20:143-159.

Appointed to the Departments of Immunology and

Paediatrics at the University of Toronto. External

support provided by Canadian Genetic Diseases

Network, Canadian Institutes of Health Research,

and Lotte & John Hecht Memorial Foundation.

Research Institute

39


Research activities

Annual Report 2000-2001

40

William Cole, Genetics & Genomic

Biology: Mutations in Ehlers-Danlos

syndrome and skeletal dysplasias

The Ehlers-Danlos syndrome produces

severe laxity of the soft connective tissues.

My laboratory’s continuing studies have

identified nonsense and missense mutations

of the type V collagen genes – COL5A1

and COL5A2. The abnormal type V

collagen impairs the formation of type 1

collagen fibrils and results in tissue laxity

and fragility. We have also identified

unique mutations of the type X collagen

in chondrodysplasia, of the sedlin gene in

spondyloepiphyseal dysplasia tarda, and

of the diastrophic sulfate transporter gene

in multiple epiphyseal dysplasia and the

EXT genes in osteochrondromas.

Wenstrup RJ, Florer JB, Willing MC, Giunta C,

Steinmann B, Young F, Susic M, Cole WG. Col5A1

haploinsufficiency is a common molecular mechanism

underlying the classical form of eds. Am J Hum Genet

2000;66:1766-1776.

Wilkin DJ, Liberfarb R, Davis J, Levy H, Cole WG,

Francomano CA, Cohn DH. Rapid determination

of COL2A1 mutations in individuals with Stickler

syndrome: analysis of potential termination codons.

Am J Med Genet 2000;94:141-148.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Canadian Institutes of Health Research and

Canadian Arthritis Network.

John Coles, Cardiovascular Research:

Xenogeneic cardiomyocyte

transplantation

As many as 35% of children requiring

heart transplantation die on the waiting

list as a result of an insufficient supply of

available human cadaveric heart donors.

My colleagues and I have pursued the

strategy of transplantation one step further:

we proposed the use of individual cardiac

muscle-cell transplantation, derived from

animal species. This provides not only an

unlimited supply of available tissue for

transplantation, but also lends itself to

gene-therapy approaches designed to

modify and reduce the inherent rejection

response. We intend to exploit the use

of novel signalling molecules that could

provide the basis for new therapeutic

interventions. This should enable successful

heart transplantation, either of the whole

organ graft or the individual muscle cell,

regardless of species origin.

West LJ, Pollock-Barziv SM, Dipchand AI, Lee KJ,

Cardella CJ, Benson LN, Rebeyka IM, Coles JG.

ABO-incompatible heart transplantation in infants.

N Engl J Med 2001;344:793-800.

Dellgren G, Koirala B, Sakopoulus A, Botta A,

Joseph J, Benson L, McCrindle B, Dipchand A,

Cardella C, Lee KJ, West L, Poirier N,

Van Arsdell GS, Williams WG, Coles JG. Pediatric

heart transplantation: improving results in

high-risk patients. J Thorac Cardiovasc Surg

2001;121:782-791.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Heart and Stroke Foundation of Ontario.

Mary Corey, Population Health

Sciences: Genetic epidemiology of

cystic fibrosis

Although cystic fibrosis (CF) is a classic

genetic disease, the severity and progression

of symptoms are extremely variable.

My research is focused on explaining this

variability in regional and national patient

populations. Survival analysis shows the

relative risks associated with many factors

like sex, mode of diagnosis, pancreatic

function, lung function, and infection.

Longitudinal regression analysis defines

the rate of decline in lung function and

its relationship to other factors, including

CFTR mutation categories and other genes

that may modify the severity of CF. These

studies produce the knowledge necessary

to develop and assess new treatments for

CF, and provide a model for studying

other complex genetic diseases.

Schneiderman-Walker J, Pollock SL, Corey M,

Wilkes DD, Canny GJ, Pedder L, Reisman JJ.

A randomized controlled trial of a 3-year home

exercise program in cystic fibrosis. J Pediatr

2000;136:304-310.

Ginzberg H, Shin J, Ellis L, Goobie S, Morrison J,

Corey M, Durie PR, Rommens JM. Segregation

analysis in Shwachman-Diamond syndrome:

evidence for recessive inheritance. Am J Hum

Genet 2000;66:1413-1416.

Appointed to the Departments of Public Health

Sciences and Paediatrics at the University of

Toronto. External support provided by Canadian

Cystic Fibrosis Foundation, Canadian Institutes

of Health Research, National Institutes of Health,

and Network of Centres of Excellence – The

Mathematics of Information Technology and

Complex Systems.

Peter Cox, Integrative Biology:

Optimizing mechanical ventilation

strategies

My colleagues and I continue to examine

optimal methods of ventilatory support for

patients with critical lung disease. In the

past year, we have focused our attention

on the use of high-frequency oscillation

and demonstrated that not only does lung

recruitment optimize gas exchange, but it

also opens up the lung and prevents the

repetitive stretch injury that aggravates

underlying pathologies. In addition, we

have demonstrated that applying a similar

philosophy of lung recruitment to conventional

mechanical ventilation achieves

a similar goal. We have also completed

work on the distribution of pulmonary

blood flow in a perfluorocarbon-filled lung.

Morris KP, Cox PN, Mazer CD, Frndova H,

McKerlie C, Wolfe R. Distribution of pulmonary

blood flow in the perfluorocarbon-filled lung.

Intensive Care Med 2000;26:756-763.

Rimensberger PC, Pache J-C, McKerlie C,

Frndova H, Cox PN. Lung recruitment and lung

volume maintenance: a strategy for improving

oxygenation and preventing lung injury during

both conventional mechanical ventilation and

high-frequency oscillation. Intensive Care Med

2000;26:745-755.

Appointed to the Departments of Anaesthesia,

Critical Care Medicine and Paediatrics at the

University of Toronto. External support provided

by Canadian Institutes of Health Research,

Heart and Stroke Foundation of Ontario, Alliance

Pharmaceutical Corp., and Ronald McDonald

Children’s Charities.

Jamie Cuticchia, Genetics &

Genomic Biology: Computational

methods for genomic curation

and sequence analysis with

supercomputing

One of my major projects is the continued

development and curation of the GDB

Human Genome Database, the official

mapping repository of the human genome

project. My colleagues and I are also

working with scores of research groups

across the world to develop a central

repository for human mutation. The year

2000 saw the opening of the Ontario

Centre for Genomic Computing (OCGC),

a significant initiative supported by the

Ontario Research and Development

Challenge Fund, SGI Canada, and the

hospital. As the largest publicly accessible

supercomputing site dedicated solely to

the life sciences, the OCGC will enable

world-class research in the field of

genomics by providing scientists with

state-of-the-art computational resources to

support and enhance current and future

biological research in Ontario.

Cuticchia AJ. Future vision of the GDB Human

Genome Database. Hum Mutat 2000;15:62-67.

Cuticchia AJ. High performance computing and

medical research. CMAJ 2000;162:1148-1149.

Appointed to the Departments of Medical

Biophysics, and Medical Genetics and Microbiology

at the University of Toronto. External support

provided by Canada Foundation for Innovation,

GlycoDesign, Neurotrophic Bioscience Inc., Ontario

Research and Development Challenge Fund, and

The Hospital for Sick Children Foundation.

Ernest Cutz, Lung Biology:

Lung O 2 sensor

My ongoing cellular and molecular

studies of the role of the pulmonary neuroendocrine

cell (PNEC) system during

normal lung development and in perinatal

lung diseases focus on two main areas.

1) As a part of the Canadian Institutes of

Health Research group on lung development,

I am investigating the role of

PNEC-derived peptides (mainly bombesin)

on lung growth and differentiation;

2) In my studies of the innervated clusters

of PNEC, I am focusing on the function of

neuroepithelial bodies (NEB) as airway O2 sensors, particularly on the membrane and

molecular mechanism (i.e., the role of the

O2-sensitive K + channel linked to the O2- sensing protein). NEB may be involved in

the regulation of breathing and neonatal

adaptation, and in a variety of paediatric

lung diseases, including bronchopulmonary

dysplasia, cystic fibrosis, and asthma.

Cutz E, Jackson A. Neuroepithelial bodies as airway

oxygen sensors. Respir Physiol 1999;115:201-214.

Fu XW, Wang D, Nurse CA, Dinauer MC, Cutz E.

NADPH oxidase is an O2 sensor in airway

chemoreceptors: evidence from K + current modulation

in wild-type and oxidase-deficient mice. Proc Natl

Acad Sci USA 2000;97:4374-4379.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Canadian

Cystic Fibrosis Foundation and Canadian Institutes

of Health Research.

Research Institute

41


Research activities

Annual Report 2000-2001

42

Denis Daneman, Population Health

Sciences: Factors affecting metabolic

control and early complications in

diabetes in childhood and

adolescence

My research focuses on 1) eating disorders

in adolescent girls with type I diabetes;

2) the natural history and pathogenesis

of early diabetes-related complications,

specifically diabetic nephropathy; and

3) the factors affecting metabolic control

in children and adolescents with diabetes.

My colleagues and I have produced

definitive evidence of the increased

prevalence of eating disorders, both clinical

and subthreshold, in teenage girls with

diabetes, and of the link between these

disorders and specific patterns of family

dysfunction. We have also shown that

the natural history of early diabetic

nephropathy in adolescents differs

from that in adults in its slower and

less predictable progression, and that early

nephropathy is dependent, in part, on

the activity of the GH-IGF-l axis. These

studies have also been expanded to include

early markers of macrovascular disease.

We are studying methods for improving

metabolic control in adolescents with

diabetes as well as outcomes of current

therapeutic approaches.

Lawson ML, Sochett EB, Frank MR, Fry MK,

Stephens D, Chait P, Daneman D. Intensive diabetes

management decreases Na-Li countertransport in

young subjects with type 1 diabetes and enlarged

kidneys. J Diabetes Complications 2000;14:333-339.

Parikh A, Sochett EB, McCrindle BW, Dipchand A,

Daneman A, Daneman D. Carotid artery

distensibility and cardiac function in adolescents

with type 1 diabetes. J Pediatr 2000;137:465-469.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Canadian Diabetes Association, Canadian Institutes

of Health Research, Eli Lilly Canada Inc, Paediatric

Consultants, National Institutes of Health, and

The Hospital for Sick Children Foundation.

Jayne Danska, Developmental

Biology: Lymphocyte development,

function, and dysfunction

My research focuses on two areas:

1) DNA-damage checkpoints in normal

and transformed lymphocytes and

2) genetic regulation of autoimmune

disease. 1) During their development,

lymphocytes undergo DNA breakage

and rejoining to create genes encoding

the cell-surface receptors that recognize

foreign organisms. Errors in this DNArepair

process can cause genetic mutations

that contribute to uncontrolled cell growth.

My colleagues and I are characterizing the

role of DNA-damage-checkpoint proteins

during lymphocyte development, and the

way errors in these processes contribute to

lymphoma and lymphocytic leukaemia.

2) Type 1 diabetes is an autoimmune

disease that occurs when the immune

system fails to be self-tolerant and destroys

the insulin-producing cells of the pancreas.

Susceptibility to type 1 diabetes involves

multiple genes, most of which are not yet

identified. Our work is focused on identifying

the genes that control the disease,

information that is essential to the design

of new therapies for prevention and cure.

Williams CJ, Grandal I, Vesprini DJ, Wojtyra U,

Danska JS, Guidos CJ. Irradiation promotes V(D)J

joining and RAG-dependent neoplastic transformation

in SCID T-cell precursors. Mol Cell Biol 2001;

21:400-413.

Fox CJ, Paterson AD, Mortin-Toth SM, Danska JS.

Two genetic loci regulate T-cell-dependent islet

inflammation and drive autoimmune diabetes

progression. Am J Hum Genet 2000;67:67-81.

Appointed to the Departments of Immunology and

Medical Biophysics at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Juvenile Diabetes Foundation

International, National Cancer Institute of Canada,

Premier’s Research Excellence Award, and

University of Toronto.

Charles Deber, Structural Biology

& Biochemistry: Disease-inducing

mutations studied by membraneprotein

engineering

Point mutations within membrane domains

can cause protein function to become

aberrant in human diseases such as cystic

fibrosis. To investigate the molecular

mechanisms underlying such impairment

of function, my colleagues and I are

expressing segments of the chloridechannel

domain of the cystic fibrosis

transmembrane conductance regulator

(CFTR). Conformations of the resulting

proteins are deduced with biochemical

and spectroscopic techniques, and

correlated with the location and type

of mutations within the CFTR transmembrane

segments. In complementary

studies, we use site-directed mutagenesis

to prepare viral coat-protein mutant libraries

and analyze designed synthetic peptides

containing membrane-interactive helices.

In the broader context, these systems serve

as models for guiding and refining the

deduction of the secondary and tertiary

structure of proteins and of helix-helixpacking

motifs within membranes.

Yuen CTK, Davidson AR, Deber CM. Role of

aromatic residues at the lipid-water interface in

micelle-bound bacteriophage M13 major coat protein.

Biochemistry 2000;39:16155-16162.

Deber CM, Wang C, Liu L-P, Prior AS, Agrawal S,

Muskat BL, Cuticchia AJ. TM Finder: a prediction

program for transmembrane protein segments using

a combination of hydrophobicity and nonpolar phase

helicity scales. Protein Sci 2001;10:212-219.

Appointed to the Department of Biochemistry at

the University of Toronto. External support

provided by Canadian Cystic Fibrosis Foundation,

Cystic Fibrosis Foundation US, Canadian Institutes

of Health Research, National Institutes of Health,

and Natural Sciences and Engineering Research

Council of Canada.

Maureen Dennis, Brain &

Behaviour Research:

Neurobehavioural outcome of

congenital and acquired brain injury

My laboratory studies two principal

questions, each supported by a US National

Institutes of Health grant. One question

concerns the neurobiology of spina bifida,

which includes studies of the genetic basis

of neural-tube closure; the early development

of infants with spina bifida; and brain

imaging, attention, coordinate movement,

and the academic skills of school-aged

children with spina bifida. The other

question concerns the neurobiology of

childhood head injury, which includes

studies (including brain imaging)

of neuropsychological functions such as

cognitive inhibition, memory, and learning

in relation to measures of the severity

of head injury. Together, these questions

provide a perspective on the neurobiological

outcome of congenital

and acquired brain injury.

Dennis M, Hetherington CR, Spiegler BJ, Barnes

MA. Functional consequences of congenital cerebellar

dysmorphologies and acquired cerebellar lesions of

childhood. In: Broman SH, Fletcher JM, editors.

The changing nervous system. New York: Oxford

University Press; 1999. p. 172-198.

Dennis M. Childhood medical disorders and

cognitive impairment: biological risk, time,

development, and reserve. In: Yeates KO, Ris MD,

Taylor HG, editors. Pediatric neuropsychology:

research, theory, and practice. New York: Guilford;

2000. p. 3-22.

Appointed to the Departments of Surgery and

Psychology, and the Institute of Medical Science

at the University of Toronto. External support

provided by National Institutes of Health.

Gabrielle deVeber, Population

Health Sciences: Canadian

Pediatric Ischemic Stroke Registry

and outcome study

I initiated and direct several large

population-based studies of childhood

stroke caused by blood clots. According

to our Canadian Pediatric Ischemic Stroke

Registry, the annual incidence of stroke

among children is at least 3.2 in every

100,000 children. The registry has studied

the frequency, causes, and recurrence of

stroke in more than 800 affected infants

and children at the 16 children’s hospitals

in Canada. Important reasons for stroke

include chicken pox and anticardiolipin

antibodies, a clotting problem. The

Bloorview Children’s Stroke Project, which

also included the Stroke Outcome Study

at The Hospital for Sick Children, has

reported recovery after stroke in 165 infants

and children. Studies of treatments for

childhood stroke are being developed.

deVeber GA, MacGregor D, Curtis R, Mayank S.

Neurological outcome in survivors of childhood

arterial ischemic stroke and sinovenous thrombosis.

J Child Neurol 2000;15:316-324.

Lanthier S, Lortie A, Michaud J, Laxer R, Jay V,

deVeber G. Isolated angiitis of the CNS in children.

Neurology 2001;56:837-842.

Appointed to the Department of Paediatrics

at the University of Toronto. External support

provided by Bloorview Childrens Hospital

Foundation, Canadian Stroke Network, Heart and

Stroke Foundation of Ontario, and The Hospital

for Sick Children Foundation.

John Dick, Cancer & Blood Research:

Characterization of normal and

leukaemic human stem cells

My colleagues and I established that

distinct classes of human haematopoietic

stem cells, termed SCID-repopulating cells

(SRC), differ in their capacity to repopulate

NOD/SCID mice. The ability to track

individual clones of human stem cells was

made possible by developing procedures

for the efficient transduction of SRC

with retrovirus and lentivirus vectors. The

gene inserted into each transduced SRC

provided a unique tag that enabled us

to determine that some SRC functioned

rapidly after transplant, but then disappeared,

whereas other SRC provided a

more stable long-term graft. This discovery

has important implications for future

clinical applications that involve stem-cell

transplantation, including gene therapy

or stem-cell engineering. The introduction

of vectors expressing human oncogenes

provided new insight into how oncogenes

function to perturb the normal developmental

program of human stem cells, resulting

in the initiation of human leukaemia.

Guenechea G, Gan OI, Inamitsu T, Dorrell C,

Pereira D, Kelly M, Naldini L, Dick JE.

Transduction of human CD34 + CD38- bone marrow

and cord blood-derived SCID-repopulating cells

with third-generation lentiviral vectors. Mol Ther

2000;1:566-573.

Guenechea G, Gan OI, Dorrell C, Dick JE. Distinct

classes of human stem cells that differ in proliferative and

self-renewal potential. Nat Immunol 2001;2:75-82.

Appointed to the Departments of Molecular and

Medical Genetics, and Medical Genetics and

Microbiology at the University of Toronto. External

support provided by Canadian Genetic Diseases

Network, Canadian Institutes of Health Research,

National Cancer Institute of Canada, and National

Institutes of Health.

Research Institute

43


Research activities

Annual Report 2000-2001

44

Paul Dick, Population Health

Sciences: The Paediatric Outcomes

Research Team

Do children need the care they get and

get the care they need? The Paediatric

Outcomes Research Team uses a

combination of clinical and health services

research to answer these questions for

childhood illnesses. All aspects of care,

such as screening, diagnosis, treatment,

and rehabilitation, may be included.

My colleagues and I are currently involved

in studies evaluating the effectiveness

of diagnostic strategies, the pattern of

hospitalization, and children’s use of

home care. The latter includes examining

the use of telecommunications technology

to deliver health care to children in remote

areas of the province and to children

receiving care at home.

Dick PT, Filler R, Pavan A. Participant

satisfaction and comfort with multidisciplinary

pediatric telemedicine consultations. J Pediatr Surg

1999;34:137-142.

Cheung JC, Dick PT, Kraft SP, Yamada J,

Macarthur C. Strabismus examination by telemedicine.

Ophthalmology 2000;107:1999-2005.

Appointed to the Departments of Paediatrics and

Health Administration at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Health Canada, Ministry of

Health and Long-Term Care, and The Hospital for

Sick Children Foundation.

Peter Dirks, Developmental

Biology: Neural stem cells and braintumour

formation

My laboratory is interested in the

relationship between normal brain

development and brain-tumour formation.

We are particularly interested in whether

stem cells found normally in the brain are

the targets for transforming events that

result in particular types of brain tumours.

We are now working with oncogenes

derived from three different tumour types

of the central nervous system to see if

they can transform normal brainstem

cells into specific types of brain tumours.

This work has implications for understanding

the early molecular events

involved in the formation of brain tumours

and for understanding the molecular

determinants of brain-tumour phenotypes.

Appointed to the Department of Surgery at the

University of Toronto. External support provided by

Canadian Institutes of Health Research, National

Cancer Institute of Canada, The Hospital for Sick

Children Foundation, and University of Toronto.

Hans-Michael Dosch, Infection,

Immunity, Injury & Repair Research:

Cell and molecular mechanisms of

autoimmunity in diabetes and

multiple sclerosis

My laboratory uses gene knock-out and

transgene models to study autoimmune

mechanisms. We directly apply our

conclusions to studies of patients with

autoimmune diabetes or multiple sclerosis

(MS), identifying mechanisms operant

in the human disease. We are a USA

immune-tolerance network. Some of our

projects are fundamental to the global

primary-diabetes prevention trial, or

TRIGR (Trial to Reduce Type I Diabetes

in the Genetically at Risk), of which

I am the basic science chair. Mapping

unexpected commonalities between

diabetes and MS and defining the central

target autoantigen in Sjøgren syndrome

are highlights of current projects.

Winer S, Gunaratnam L, Astsatourov I, Cheung

RK, Kubiak V, Karges W, Hammond-McKibben D,

Gaedigk R, Graziano D, Trucco M, Becker DJ,

Dosch, HM. Peptide dose, MHC affinity, and target

self-antigen expression are critical for effective

immunotherapy of non-obese diabetic mouse

prediabetes. J Immunol 2000;165:4086-4094.

Winer S, Astsatourov I, Cheung RK, Gunaratnam

L, Kubiak V, Cortez MA, Moscarello M, O’Connor

PW, McKerlie C, Becker DJ, Dosch, HM. Type I

diabetes and multiple sclerosis patients target islet

plus central nervous system autoantigens; nonimmunized

nonobese diabetic mice can develop

autoimmune encephalitis. J Immunol. 2001;166:

2831-2841.

Appointed to the Departments of Paediatrics and

Immunology at the University of Toronto. External

support provided by Canadian Diabetes Association,

Canadian Institutes of Health Research, Juvenile

Diabetes Foundation International, and SynX

Pharma Inc.

James Drake, Brain & Behaviour

Research: Hydrocephalus research

Hydrocephalus, an abnormal accumulation

of spinal fluid within the fluid-containing

spaces of the brain, is very common in

children. Hydrocephalus is normally treated

with a valved drainage tube called a shunt,

50% of which stop working in 2 years. In

the hydrocephalus research program, my

colleagues and I focus on clinical and basic

research into the reasons for shunt failure.

This research includes randomized trials

for new shunt valves and surgical insertion

techniques such as the use of miniature

scopes, prospective studies of shunt failure,

looking at the risk factors for failure, a

prospective study of shunt infection,

and the development of clinical outcome

measures for children with hydrocephalus.

Our basic research focuses on the development

of minimally invasive techniques for

unblocking shunts and on the development

of mathematical models of the

hydrocephalic brain for improved shuntvalve

design and placement.

Tenti G, Drake JM, Sivaloganathan S. Brain

biomechanics: mathematical modelling of

hydrocephalus. Neurol Res 2000;22:19-24.

Tuli S, Drake J, Lawless J, Wigg M,

Lamberti-Pasculli M. Risk factors for repeated

cerebrospinal shunt failures in pediatric patients

with hydrocephalus. J Neurosurg 2000;92:31-38.

Appointed to the Departments of Surgery and

Biomedical Engineering, and the Institute of

Medical Science at the University of Toronto.

External support provided by The Hospital for

Sick Children Foundation and The Physicians’

Services Incorporated Foundation.

Yigal Dror, Infection, Immunity,

Injury & Repair Research: The role

of apoptosis in the pathogenesis of

marrow failure in inherited bone

marrow-failure syndromes

Inherited bone marrow-failure syndromes

are characterized by varying degrees of

cytopenia. The molecular basis for bone

marrow failure is known in only a minority

of the disorders. My research has been

focused on the pathogenesis of bone

marrow failure in these conditions and

especially on the role of apoptosis. I have

recently shown that Shwachman-Diamond

syndrome haematopoietic progenitors

are intrinsically flawed: they have faulty

proliferative properties and increased

apoptosis. This increased propensity for

apoptosis was linked to the hypersensitivity

of the Fas pathway and higher Fas

expression on marrow cells from patients

at all stages of maturation.

Dror Y, Freedman MH. Shwachman-Diamond

syndrome: an inherited preleukemic bone marrow

failure disorder with aberrant hematopoietic

progenitors and faulty marrow microenvironment.

Blood 1999;94:3048-3054.

Dror Y, Freedman MH. Shwachman-Diamond

syndrome marrow cells show abnormally increased

apoptosis mediated through the Fas pathway.

Blood 2001;97:3011-3016.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by The Hospital for Sick Children Foundation.

Peter Durie, Integrative Biology:

Disorders of the exocrine pancreas

in childhood

The research in my laboratory focuses

on the pathogenesis of exocrine pancreatic

disorders in infancy and childhood. Much

of this work is done on cystic fibrosis and

Shwachman-Diamond syndrome, the most

common inherited causes of exocrine

pancreatic disease in childhood. One goal

of our current studies is to understand the

clinical, biological, and functional consequences

of mutations in the cystic fibrosis

transmembrane conductance regulator

(CFTR), the gene defective in patients with

cystic fibrosis. A second goal is to

understand the relationship between the

functional classes of CFTR-gene mutations

and the expression of the basic defect

in vivo. In collaboration with

Dr. Johanna Rommens, we are evaluating

the clinical phenotype and genetic basis

of Shwachman-Diamond syndrome.

Ginzberg H, Shin J, Ellis L, Morrison J, Ip W,

Dror Y, Freedman M, Heitlinger LA, Belt MA,

Corey M, Rommens JM, Durie PR. Shwachman

syndrome: phenotypic manifestations of sibling sets

and isolated cases in a large patient cohort are

similar. J Pediatr 1999;135:81-88.

Goobie S, Popovic M, Morrison J, Ellis L,

Ginzberg H, Boocock GR, Ehtesham N, Betard C,

Brewer CG, Roslin NM, Hudcon TJ, Morgan K,

Fujiwara TM, Durie PR, Rommens JM.

Shwachman-Diamond syndrome with exocrine

pancreatic dysfunction and bone marrow failure

maps to the centromeric region of chromosome 7.

Am J Hum Genet 2001;68:1048-1054.

Appointed to the Department of Paediatrics

and the Institute of Medical Science at the

University of Toronto. External support provided by

Canadian Cystic Fibrosis Foundation, Canadian

Institutes of Health Research, Digestive Care Inc.,

National Institutes of Health, Organon Canada Ltd.,

Paediatric Consultants, Shwachman Diamond Syndrome

Canada Inc., and Solvay Pharmaceuticals GmbH.

Research Institute

45


Research activities

Annual Report 2000-2001

46

Sean Egan, Developmental Biology:

Notch regulation of mammary

development and Ese regulation of

receptor endocytosis and signalling

My laboratory studies two topics. First,

we are interested in how Notch activation

is used to control the development of

mouse mammary glands. We are currently

studying the development of mammary

glands and breast cancer in several

transgenic and mutant mouse strains

to determine precisely what role Notch

ligands and Fringe proteins play in the

regulation of mammary epithelial

patterning and differentiation. These

studies are complemented by in vitro

analysis of Notch-receptor activation.

Second, we have identified a conserved

family of adapter proteins that control

receptor endocytosis and signalling.

We are currently analyzing the function

of Ese proteins biochemically and

through gene-targeting in mice.

Sengar AS, Wang W, Bishay J, Cohen S, Egan SE.

The EH and SH3 domain Ese proteins regulate

endocytosis by linking to dynamin and Eps 15.

EMBO J 1999;18:1159-1171.

Singh N, Phillips RA, Iscove NN, Egan SE.

Expression of notch receptors, notch ligands and

fringe genes in hematopoiesis. Exp Hematol

2000;28:527-534.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Apotex Research

Inc., Canadian Institutes of Health Research,

and National Cancer Institute of Canada.

James Ellis, Developmental

Biology: Gene silencing in stem

cells, and blood gene therapy

vector development

Gene therapy for blood diseases involves

gene transfer into stem cells, but is

hindered by low gene-expression levels.

Stem cells silence retrovirus vectors by

compacting DNA into inaccessible

chromatin structures. My colleagues and

I are characterizing retrovirus-silencing

pathways in flies, mice, and embryonic

stem cells. Retrovirus vectors that resist

silencing are being enhanced with insulator

elements that block silent chromatin

and with modified reporter genes that

escape silencing. We have developed novel

β-globin transgenes for gene therapy for

β-thalassaemia, and we are now studying

the DNA elements that control β-globin

gene expression and the initiation of DNA

replication. These approaches provide

insight into gene silencing, gene expression,

and DNA replication, and may culminate

in improved vectors for gene therapy of

stem cells.

Pannell D, Osborne CS, Yao S, Sukonnik T, Pasceri

P, Karaiskakis A, Okano M, Li E, Lipshitz HD,

Ellis J. Retrovirus vector silencing is de novo

methylase independent and marked by a repressive

histone code. EMBO J 2000;19:5884-5894.

Rubin JE, Pasceri P, Wu X, Leboulch P, Ellis J. Locus

control region activity by 5’HS3 requires a functional

interaction with β-globin gene regulatory elements:

expression of novel β/γ-globin hybrid transgenes.

Blood 2000;95:3242-3249.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Juvenile Diabetes Foundation

International, and The Hospital for Sick

Children Foundation.

Brian Feldman, Population Health

Sciences: Clinical research in

paediatric rheumatic disease

My work focuses on two main areas:

1) practical studies of new therapies for

rheumatic illness and 2) methods for

improving the study of rare diseases.

My colleagues and I are continuing with

the implementation and development of

several national and international clinical

trials examining the costs and effectiveness

of prophylactic factor replacement for

patients with haemophilic arthritis. We

also have ongoing studies examining the

usefulness of alternative clinical trial

designs, including Bayesian meta-analysis

of N-of-1 studies. We have recently

reported on the use of methotrexate as

a first-line treatment for patients with

juvenile dermatomyositis. We are

continuing our investigations to find the

best methods of evaluating the health-state

values for children with musculoskeletal

disease and chronic illness.

Spiegel LR, Schneider R, Lang BA, Birdi N,

Silverman ED, Laxer RM, Stephens D, Feldman

BM. Early predictors of poor functional outcome

in systemic-onset juvenile rheumatoid arthritis.

A multicenter cohort study. Arthritis Rheum

2000;43:2402-2409.

Huber AM, Lang B, LeBlanc CMA, Birdi N,

Bolaria RK, Malleson P, MacNeil I, Momy JA,

Avery G, Feldman BM. Medium- and long-term

functional outcomes in a multicenter cohort of

children with juvenile dermatomyositis. Arthritis

Rheum 2000;43:541-549.

Appointed to the Departments of Paediatrics,

Public Health Sciences, and Health Administration

at the University of Toronto. External support

provided by Aventis Behring Canada Inc., Bayer

Inc., Canadian Institutes of Health Research,

Paediatric Consultants, and The Arthritis Society.

Julie Forman-Kay, Structural Biology

& Biochemistry: Determination of

the structure and dynamics of

signalling proteins with nuclear

magnetic resonance spectroscopy

Many biological processes such as growth

and differentiation are mediated by protein

interactions involving modular-binding

domains. These domains, including the

SH2, SH3, PTB, and WW domains,

recognize specific protein sequences and

structural motifs. My colleagues and

I are interested in the mechanism of this

recognition. We use nuclear magnetic

resonance spectroscopy to determine the

structures and the dynamic properties of

these domains in complexes with their

target proteins. In addition, we are studying

the disordered states that often occur in

the absence of a target-binding partner.

This research provides insights into the

molecular bases of cancer and other

diseases that result from the deregulation

of signalling pathways.

Zwahlen C, Li S-C, Kay LE, Pawson T,

Forman-Kay JD. Multiple modes of peptide

recognition by the PTB domain of the cell fate

determinant Numb. EMBO J 2000;19:1505-1515.

Mok Y-K, Kay CM, Kay LE, Forman-Kay J.

NOE data demonstrating a compact unfolded state

for an SH3 domain under non-denaturing

conditions. J Mol Biol 1999;289:619-638.

Appointed to the Department of Biochemistry

at the University of Toronto. External support

provided by Canada Foundation for Innovation,

Canadian Cystic Fibrosis Foundation, Canadian

Institutes of Health Research, National Cancer

Institute of Canada, Ontario Innovation Trust,

and Premier’s Research Excellence Award.

Christopher Forrest, Developmental

Biology: Development of

cytoprotective strategies for the

prevention of radiation-induced

craniofacial bone-growth retardation

Radiation-induced craniofacial deformities

are common after growing children with

head and neck cancers receive combination

treatment that involves radiation therapy.

To date, the mechanism of radiationinduced

craniofacial bone-growth

retardation has not been adequately

investigated, and the treatment of these

deformities, once established, is quite

unsatisfactory. My laboratory has developed

an animal model of radiation-induced

craniofacial bone-growth inhibition using

the infant rabbit and is currently studying

the role of cytoprotective strategies for the

prevention of craniofacial bone-growth

retardation. Investigations are currently

underway at a cellular and molecular

level to understand the mechanism of

radiation injury to growing craniofacial

bone. We hope that this work will lead to

effective radioprotective strategies for

the prevention of radiation-induced

craniofacial-bone deformities in children

with head and neck cancers.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Canadian Institutes of Health Research, Plastic

Surgery Educational Foundation, Synthes (Canada)

Ltd., Synthes (USA).

Janet Forstner, Structural Biology

& Biochemistry: Intestinal mucus

glycoproteins and lung infections

in cystic fibrosis

Secretory mucins cover the internal linings

of the body to provide lubrication and

protection. My laboratory studies the

molecular features of secreted mucins

to determine how they develop gel-like

abnormalities in the disease cystic fibrosis

(CF). Cell membrane-associated mucins

normally play important roles in organ

growth and maturation, but are also key

players in the development of cancer

and the evasion of the immune system.

Recently, we have shown that specific

membrane mucins are also released from

their membrane tether and help cause the

intestinal problems of CF. In a separate

project, we are identifying the steps

responsible for the fatal CF lung infections

caused by virulent strains of the bacteria

Burkholderia cepacia. We have shown

that these bacteria attach to airway cells

by special threads (pili) and invade the

lung by passing into and between airwaylining

cells.

Xu G, Bell SL, McCool D, Forstner JF. The cationic

C-terminus of rat Muc2 facilitates dimer formation

post translationally and is subsequently removed by

furin. Eur J Biochem 2000;267:2998-3004.

Sajjan U, Wu Y, Kent G, Forstner J. Preferential

adherence of cable-piliated Burkholderia cepacia to

respiratory epithelia of CF knockout mice and human

cystic fibrosis lung explants. J Med Microbiol

2000;49:875-885.

Appointed to the Department of Biochemistry

at the University of Toronto. External support

provided by Canadian Cystic Fibrosis Foundation

and Canadian Institutes of Health Research.

Research Institute

47


Research activities

Annual Report 2000-2001

48

Melvin Freedman, Infection,

Immunity, Injury & Repair Research:

Malignant myeloid transformation

in genetic forms of neutropenia

Patients with inherited neutropenia, such

as Shwachman syndrome and Kostmann

syndrome, have a striking predisposition

for myelodysplasia and acute myeloblastic

leukaemia (MDS/AML). The goals of

the research for my laboratory are to

determine the cellular and molecular basis

for defective bone-marrow function in

these disorders and to see if those who

develop MDS/AML can be identified

before overt transformation, which will

allow early medical intervention.

Freedman MH, Bonilla MA, Fier C, Bolyard AA,

Scarlata D, Boxer LA, Brown S, Cham B,

Kannourakis G, Kinsey SE, Mori PG, Cottle T,

Welte K, Dale DC. Myelodysplasia syndrome and

acute myeloid leukemia in patients with congenital

neutropenia receiving G-CSF therapy. Blood

2000;96:429-436.

Dror Y, Ward AC, Touw I, Freedman MH.

Combined corticosteroid/granulocyte colonystimulating

factor (G-CSF) therapy in the treatment

of severe congenital neutropenia unresponsive

to G-CSF: activated glucocorticoid receptors synergise

with G-CSF signals. Exp Hematol 2000;28:

1381-1389.

Appointed to the Department of Paediatrics at

the University of Toronto. External support

provided by Amgen Inc., Lotte & John Hecht

Memorial Foundation, Paediatric Consultants,

Shwachman Diamond Syndrome Canada Inc., and

The Hospital for Sick Children Foundation.

Katryn Furuya, Cancer & Blood

Research: Regulation and

expression of the new ATP-binding

cassette transporter P-glycoproteinrelated

protein

P-glycoprotein-related protein (PRP) is a

new member of the ATP-binding cassette

family of transporters. What function or

role PRP plays within the cell is unknown;

what is known is that more PRP is present

in human liver cancers than in normal

human liver. It is possible that, like the

closely related P-glycoproteins, PRP plays

a role in drug resistance in cancer cells.

The aim of my work is 1) to determine the

controls that regulate the amount of PRP

in cells, 2) to identify partner proteins that

combine with PRP to form a functional

transporter, and 3) to determine the

function or role that PRP plays in normal

and in cancerous cells.

Appointed to the Departments of Paediatrics and

Pharmacology, and the Institute of Medical Science

at the University of Toronto. External support

provided by Canadian Institutes of Health Research

and National Cancer Institute of Canada.

Susan Goldberg, Integrative Biology:

Developmental psychopathology:

The role of early attachment

My team studies the parent-infant

relationship as a bio-behavioural system

that serves as a buffer between the infant’s

internal physiological processes and

external stressors. Our early studies

examined the effects of different medical

conditions (which affect the infant’s

physiology) on the development of the

parent-infant relationship and the child’s

development, particularly vulnerability

to behaviour disorders. These included

studies of children born prematurely, and

those with developmental delays, cystic

fibrosis, and congenital heart disease.

Our current studies focus on 1) the way

in which the quality of parent-infant

relationships (attachment) shapes early

expression of emotion, and regulation,

cognition, and physiological stress

responses, and 2) the analysis of maternal

behaviours that disrupt the development

of early attachment in clinical and

nonclinical families.

Atkinson L, Chisholm VC, Scott B, Goldberg S,

Vaughn B, Blackwell J, Dickens S, Tam S. Atypical

attachment in infancy and early childhood among

children at developmental risk. III. Maternal

sensitivity, child functional level, and attachment

in Down syndrome. Monogr Soc Res Child Dev

1999;64:45-66.

Goldberg S, Grusec J, Jenkins JM. Confidence in

protection: arguments for a narrow definition of

attachment. J Fam Psychol 1999;13:475-483.

Appointed to the Departments of Psychiatry and

Psychology at the University of Toronto. External

support provided by Ontario Mental Health

Foundation and Psychiatry Endowment Fund.

Denis Grant, Genetics & Genomic

Biology: Molecular pharmacogenetics

of human drug-metabolizing enzymes

Pharmacogenetics is the study of the role

of inheritance in the variation of individual

human response to medications and to

chemicals in the environment. Such

variation has important implications for

therapy for disease, toxicology, and the

development of new drugs. The recognition

of the important health and commercial

implications of pharmacogenetic variation

has spawned the new discipline of

pharmacogenomics – the use of emerging

genomic technologies of target-gene

discovery, sequencing, and genotyping

to optimize the development of more

effective drug therapies. My colleagues

and I are studying the molecular

mechanisms that produce phenotypic

polymorphisms in the enzymes responsible

for converting drugs and other foreign

chemicals into more easily excreted

metabolites. Such polymorphisms may

produce alterations in drug pharmacokinetics

that can result in drug overdose,

therapeutic failure, or predisposition to

chemically induced cancers.

Grant DM. Pharmacogenomics and the changing

face of clinical pharmacology. Can J Clin Pharmacol

1999;6:131-132.

Appointed to the Departments of Paediatrics,

Pharmacology, and Pharmacy at the University of

Toronto. External support provided by Canadian

Institutes of Health Research and National Cancer

Institute of Canada.

Anne Griffiths, Infection,

Immunity, Injury & Repair Research:

Clinical research in inflammatory

bowel disease

Genetic predisposition seems particularly

important in the pathogenesis of

paediatric-onset inflammatory bowel

disease (IBD). In collaboration with

colleagues at Mount Sinai Hospital, my

research team has assembled a large

collection of DNA samples from families

in which two or more siblings are affected

with IBD, and from any affected child

and both parents. Total genome scanning

has identified a linkage of susceptibility

for early-onset Crohn disease to a novel

chromosomal site, which we are now

exploring further. As genes conferring

susceptibility to IBD are elucidated, we

hope that our paediatric IBD database

will eventually facilitate phenotypegenotype

correlations. Meanwhile, we also

continue to focus on the aspects of IBD

of special importance to young patients,

including the characterization of

long-term outcomes, and to develop

protocols for the evaluation of emerging

biological therapies.

Rioux JD, Silverberg MS, Daly MJ, Steinhart AH,

McLeod RS, Griffiths AM, Bull SB, Lander ES,

Hudson TJ, Simovitch KA. Genomewide search in

Canadian families with inflammatory bowel disease

reveals two novel susceptibility loci. Am J Hum

Genet 2000;66:1863-1870.

Otley A, Loonen H, Parekh N, Corey M, Sherman

PM, Griffiths AM. Assessing activity of pediatric

Crohn’s disease: which index to use? Gastroenterology

1999;116:527-531.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Crohn’s & Colitis Foundation of Canada,

Paediatric Consultants, and The Hospital for Sick

Children Foundation.

Sergio Grinstein, Cell Biology:

Mechanisms of microbial killing

by leucocytes

Neutrophils and macrophages constitute

the first line of defence against microorganisms.

These cells ingest and subsequently

destroy bacteria and other foreign

organisms, preventing infection. My

colleagues and I continue to study the

molecular mechanisms underlying

ingestion (phagocytosis) and elimination

of infectious particles. We have devised

means of tracking the behaviour of defined

lipids or proteins inside intact cells during

phagocytosis; individual molecules tagged

with a fluorescent probe are detected with

a powerful imaging setup. Our recent

studies revealed the exquisite segregation

of certain proteins and the localized,

transient metabolism of lipids that signal

phagosome formation. Certain

microorganisms interfere with the

formation or maturation of phagosomes,

becoming highly infectious intracellular

parasites. We have started studies to

elucidate the alterations in leucocyte

metabolism induced by microbes.

Bajno L, Peng X-R, Schreiber AD, Moore H-P,

Trimble WS, Grinstein S. Focal exocytosis of

VAMP3-containing vesicles at sites of phagosome

formation. J Cell Biol 2000;149:697-706.

Botelho RJ, Teruel M, Dierckman R, Anderson R,

Wells A, York JD, Meyer T, Grinstein S. Localized

biphasic changes in phosphatidylinositol-4,5biphosphate

at sites of phagocytosis. J Cell Biol

2000;151:1353-1367.

Holder of the Pitblado Chair in Cell Biology

at The Hospital for Sick Children. Appointed to

the Department of Biochemistry and the Institute

of Medical Science at the University of Toronto.

External support provided by Canada Foundation

for Innovation, Canadian Arthritis Network,

Canadian Cystic Fibrosis Foundation, Canadian

Institutes of Health Research, Howard Hughes

Medical Institute, National Sanatorium Association,

Ontario Innovation Trust, The Arthritis Society,

and The Hospital for Sick Children Foundation.

Research Institute

49


Research activities

Annual Report 2000-2001

50

Gil Gross, Cardiovascular Research:

Repolarizing currents in cardiac

and pulmonary arterial myocytes

My colleagues and I study the cellular

mechanisms governing the relaxation

of heart-muscle cells after each heartbeat.

These mechanisms involve the rapid

movement of charged ions across the cell

membrane, regulating many aspects of

cell activity, including the maintenance of

normal heart rhythm. We have developed

a novel model of heart block, a condition

encountered in patients of all ages that

can be associated with life-threatening

disturbances in heart rhythm. This model

is yielding new observations about the

response of heart-muscle cells to alterations

in normal cardiac electrical activity.

In collaboration with Dr. Marlene

Rabinovitch, we are also assessing the

interactions between repolarizing ionic

currents and the structural changes

observed in pulmonary hypertension,

a serious and sometimes fatal condition.

Gilbert JD, Cahill SA, McCartney DG, Lukas A,

Gross GJ. Predictors of Torsades de Pointes in

rabbit ventricles perfused with sedating and

nonsedating histamine H1-receptor antagonists.

Can J Physiol Pharmacol 2000;78:407-414.

Appointed to the Department of Paediatrics at

the University of Toronto. External support

provided by Paediatric Consultants.

Abhijit Guha, Cancer & Blood

Research: Growth regulation

of nervous system tumours

My laboratory investigates the growth

factors, receptors, and signalling pathways

that are involved in the growth of tumours

of the central and peripheral nervous

system. The growth properties examined

include proliferation, angiogenesis, cell

death, and invasion. We use a variety of

molecular biological techniques, including

cell cultures, xenografts and operative

specimens, and also develop transgenic

models. Through a better molecular

understanding, complemented by appropriate

models, we hope to be able to

develop better cures for adults and children

afflicted with these nervous system tumours.

Feldkamp MM, Lau N, Guha A. Growth inhibition

of astrocytoma cells by farnesyl transferase inhibitors

is mediated by a combination of anti-proliferative,

pro-apoptotic and anti-angiogenic effects. Oncogene

1999;18:7514-7526.

Angelov L, Salhia B, Roncari L, McMahon G,

Guha A. Inhibition of angiogenesis by blocking of

the vascular endothelial growth factor receptor leads

to decreased growth of neurogenic sarcomas. Cancer

Res 1999;59:5536-5541.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by American Brain Tumor Association, American

College of Radiology, Canadian Institutes of

Health Research, Heart and Stroke Foundation

of Ontario, National Cancer Institute of Canada,

Premier’s Research Excellence Award, and The

Cancer Research Society Inc.

Cynthia Guidos, Developmental

Biology: Molecular mechanisms

of lymphocyte development

My research program aims to define basic

mechanisms of lymphocyte development

relevant to lymphoid neoplasia, immune

deficiencies, and autoimmunity. I have

established two major research initiatives:

1) to characterize DNA repair pathways

and DNA-damage checkpoints that

limit the oncogenic potential of antigenreceptor

rearrangement in lymphocyte

precursors and 2) to define the functions

of the Notch receptors in regulating the

development of T and B lymphocytes.

Dr. Jayne Danska is a co-investigator

on the first research area.

Williams CJ, Grandal I, Vesprini DJ, Wojtyra U,

Danska JS, Guidos CJ. Irradiation promotes V(D)J

joining and RAG-dependent neoplastic transformation

in SCID T-cell precursors. Mol Cell Biol

2001;21:400-413.

Appointed to the Department of Immunology

at the University of Toronto. External support

provided by Canadian Institutes of Health Research

and National Cancer Institute of Canada.

Robert Hamilton, Cardiovascular

Research: Pathophysiology of

congenital complete heart block

My research team seeks to identify the

pathophysiology of congenital complete

heart block, a serious consequence of

immune-mediated cardiac conductionsystem

injury manifest in the fetuses and

children of mothers with clinical and

subclinical autoimmune disease. Our

multifaceted approach includes clinical

epidemiological and serological studies,

applied methods of fetal electrocardiography,

and basic science aspects of

animal and tissue modelling. Most recently,

we have developed measurable animal

models of this disease using Langendorff

rabbit hearts, autoimmunized mice, and

isolated atrioventricular nodal cells. The

electrophysiology of the disease is being

explored with assessments of Wenckebach

cycle length (a measure of atrioventricular

conduction), embryonic cardiac Doppler,

and single-cell currents. Processes in each

model can be manipulated to determine if

they are intrinsic to the pathophysiology.

Gillis AM, Hamilton RM, LeFeuvre CA. Unusual

causes of sudden cardiac death due to ventricular

tachyarrhythmias. Can J Cardiol 2000;16(Suppl

C):34C-40C.

Dipchand AI, McCrindle BW, Gow RM,

Freedom RM, Hamilton RM. Accuracy of surface

electrocardiograms for differentiating children

with hypertrophic cardiomyopathy from normal

children. Am J Cardiol 1999;15:83:628-630.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Canadian Institutes of Health Research, and The

Hospital for Sick Children Foundation.

Gregory Hannigan, Cell Biology:

Integrin-linked kinase, an essential

mediator of branching morphogenesis

and myoblast differentiation

My laboratory is interested in signal

transduction by integrin-adhesion

receptors. We have recently identified

the protein phosphatase ILKAP that

interacts with the integrin-linked kinase

ILK1. ILKAP antagonizes ILK1 signalling

to inhibit the transcriptional coactivator

β-catenin. We have also discovered that

ILK1 is required for the differentiation

of L6 myoblasts, providing a model cell

system in which to study ILK1 signal

transduction and muscle development.

We are now studying the role of ILKAP

in myoblast differentiation. In collaboration

with Dr. Norman Rosenblum (Division of

Nephrology), we have also determined that

ILK1 activity is important for induction

of branching morphogenesis in kidney

epithelial cells.

Dedhar S, Williams B, Hannigan G. Integrin-linked

kinase (ILK): a regulator of integrin and growth

factor signalling. Trends Cell Biol 1999;9:319-323.

Leung-Hagesteijn C, Mahendra A, Naruszewicz I,

Hannigan GE. Modulation of integrin signal

transduction by ILKAP, a protein phosphatase 2C

associating with the integrin-linked kinase, ILK1.

EMBO J 2001;20:2160-2170.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Canadian

Institutes of Health Research, Heart and Stroke

Foundation of Ontario, Kinetek Pharmaceuticals

Inc, and National Cancer Institute of Canada.

Patricia Harper, Developmental

Biology: Structure and function of

the aromatic hydrocarbon receptor

The aromatic hydrocarbon (Ah) receptor

is a ligand-dependent transcription factor

that plays a role in cell proliferation

and differentiation, especially during

development, and also mediates the toxic

effects of a variety of environmentally

important carcinogens, including compounds

such as 2,3,7,8-tetrachlorodibenzop-dioxin

(TCDD). Currently, the focus

of research in my laboratory is on two

main areas of Ah-receptor function:

1) the structure and function of the human

Ah receptor and 2) the ontogeny and

developmental regulation of Ah receptormediated

gene transcription in the mouse

embryo. For the first area of research, our

major goal is to identify the genetic

polymorphisms in human AHR and

to determine the way these contribute

to interindividual differences in susceptibility

to certain forms of chemically

induced cancer. In the second, we use a

variety of techniques to examine the tissue

distribution and functionality of embryonic

and fetal mouse Ah receptors.

Wong JMY, Harper P, Meyer UA, Bock KW,

Morike K, Lagueux J, Ayotte P, Tyndale RF,

Sellers EM, Manchester DK, Okey AB. Ethnic

variability in the allelic distribution of human aryl

hydrocarbon receptor codon 554 and assessment of

variant receptor function in vitro. Pharmacogenetics

2001;11:85-94.

Wolff S, Harper PA, Wong JM, Mostert V,

Wang Y, Abel J. Cell-specific regulation of human

aryl hydrocarbon receptor expression by transforming

growth factor-β1. Mol Pharmacol 2001;59:716-724.

Appointed to Departments of Paediatrics and

Pharmacology at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Health Canada, and National

Cancer Institute of Canada.

Research Institute

51


Research activities

Annual Report 2000-2001

52

Robert Harrison, Brain & Behaviour

Research: The auditory system:

How does it develop, function,

and sometimes fail?

My research explores aspects of hearing at

all levels, from the mechanical function

of the inner ear, to the neural processing

of complex sound signals in the auditory

cortex, to behavioural performance. I am

interested in the fundamental aspects of

auditory physiology and more applied

clinical problems related to hearing loss

in children. In my basic science research,

I use electrophysiology, brain imaging,

and microscopy to investigate how sounds

are actually represented within the brain,

namely the basis for the percepts of sound

that we call hearing. In my applied research,

I am interested in developing diagnostic

techniques for assessing hearing loss,

particularly in children. I also look at

how children with cochlear implants

develop their understanding of speech

and their language skills.

Harel N, Mori N, Sawada S, Mount RJ,

Harrison RV. Three distinct auditory areas of cortex

(AI, AII, AAF) defined by optical imaging of

intrinsic signals. NeuroImage 2000;11:302-312.

Stanton SG, Harrison RV. Projections from the

medial geniculate body to primary auditory cortex

in neonatally deafened cats. J Comp Neurol

2000;426:117-129.

Appointed to the Departments of Otolaryngology

and Physiology, the Institute of Medical Science,

and the Institute of Biomaterials and Biomedical

Engineering at the University of Toronto. External

support provided by Canadian Institutes of Health

Research, Masonic Foundation of Ontario, and

The Hearing Foundation of Canada.

Mark Henkelman, Integrative

Biology: Mouse imaging

With the completion of the human

and mouse genome sequence, the major

question now becomes how this detailed

genetic information is expressed in

mammals. Much of the answer will be

worked out in the mouse as a model system

for human disease. I am developing a

mouse imaging centre that will characterize

the anatomy and function of large numbers

of mice with deliberately changed genomes

using magnetic resonance imaging,

computed tomography, ultrasound, optical

imaging – all adapted for three-dimensional

characterization in high resolution.

The centre will follow the time course of

normal development and the progression

of disease and response to treatment in

individual mice. The centre has been

planned and funded; the facility should

become operational by the end of 2001.

Stanisz GJ, Kecojevic A, Bronskill MJ,

Henkelman RM. Characterizing white matter

with magnetization transfer and T2. Magn Reson

Med 1999;42:1128-1136.

Peters RD, Chan E, Trachtenberg J, Jothy S,

Kapusta L, Kucharczyk W, Henkelman RM.

Magnetic resonance thermometry for predicting

thermal damage: an application of interstitial laser

coagulation in an in vivo canine prostate model.

Magn Reson Med 2000;44:873-883.

Holder of a Tier I Canada Research Chair.

Appointed to the Departments of Medical

Biophysics and Medical Imaging at the University

of Toronto. External support provided by

Burroughs Wellcome Fund, Canada Foundation for

Innovation, Canadian Institutes of Health

Research, National Cancer Institute of Canada,

and Ontario Innovation Trust.

Elise Héon, Genetics & Genomic

Biology: Molecular characterization

of inherited eye disorders

My research involves the genetic mapping

and candidate-gene analysis of the genes

involved in inherited eye disorders, most

specifically in glaucoma, cataracts, and

retinal dystrophies. I work with patients

and families affected by specific eye

disorders to identify the disease-causing

genes and to better understand their

function. My laboratory has been successful

in identifying new genes and clarifying

their role in specific eye disorders. A

better understanding of these genes should

clarify their malfunction and potentially

lead to newer treatments. Improved

understanding also allows earlier diagnosis

of conditions such as glaucoma and

minimizes the related visual loss by

developing new therapies.

Héon E, Paterson AD, Fraser M, Billingsley G,

Priston M, Balmer A, Schorderet DF, Verner A,

Hudson TJ, Munier FL. A progressive autosomal

recessive cataract locus maps to chromosome

9q13-q22. Am J Hum Genet 2001;68:772-777.

Héon E, Priston M, Schorderet DF, Billingsley GD,

Girard PO, Lubsen N, Munier FL. The gamma

crystallins and human cataracts: a puzzle made

clearer. Am J Hum Genet 1999;65:1261-1267.

Appointed to the Department of Ophthalmology at

the University of Toronto.

Ross Hetherington, Brain &

Behaviour Research: Factors

affecting learning and cognition

My research interests are twofold:

1) cognitive timing mechanisms and

2) the relations between the dysmorphology

of the cerebellum and midbrain,

and visuospatial function and adaptive

learning. I also have a clinically focused

interest in the neurocognitive and

psychosocial function of patients with

sickle cell disease.

Hetherington CR, Dennis M. Motor function

profile in children with early onset hydrocephalus.

Dev Neuropsychol 1999;15:25-52.

Appointed to the Department of Psychology

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research and National Institutes of Health.

Aleksander Hinek, Cardiovascular

Research: Biological roles of the

elastin receptor

My colleagues and I have established

that contact between numerous cell types

and elastin is maintained by the elastinbinding

protein (EBP), which is identical

to the catalytically inactive splice variant of

β-galactosidase. We found that EBP also

plays a crucial role in elastic-fibre assembly

and is involved in the transduction of the

mitogenic signals induced by soluble

elastin-derived peptides. Thus, primary or

secondary deficiencies in the EBP can be

linked to impaired elastin deposition and

pathological processes ranging from cancer

spreading to occlusive arterial thickening

in arteriosclerosis. Most importantly, we

have determined that the accumulation

of small elastin-derived peptides is linked

to heightened cellular proliferation and,

conversely, that forced contact with insoluble

elastin induces signals that inhibit

the cell cycle. Recently, we determined

that impaired assembly of elastic fibres

contributes to the development of the

cardiovascular defects and skeletal deformities

observed in children with such inherited

conditions as Costello syndrome,

Morquio B disease, GM1-gangliosidosis, and Hurler disease.

Hinek A, Wilson SE. Impaired elastogenesis in

Hurler disease. Dermatan sulfate accumulation linked

to deficiency in elastin-binding protein and elastic

fiber assembly. Am J Pathol 2000;156:925-938.

Hinek A, Smith AC, Cutiongco EM, Callahan JW,

Gripp KW, Weksberg R. Decreased elastin deposition

and high proliferation of fibroblasts from Costello

syndrome are related to functional deficiency in the

67-kD elastin-binding protein. Am J Hum Genet

2000;66:859-872.

Appointed to the Department Laboratory

Medicine and Pathobiology, and the Institute of

Medical Science at the University of Toronto.

External support provided by Canadian Institutes of

Health Research and Heart and Stroke Foundation

of Ontario.

Hans Hitzler, Developmental

Biology: Function of translocationassociated

fusion proteins in

childhood leukaemia

Chromosomal translocations in childhood

acute lymphoblastic and acute myelogenous

leukaemia have proved important in

guiding risk-based treatment. By pointing

to a group of genes encoding transcription

factors and protein tyrosine kinases,

they also continue to focus efforts aimed

at the mechanisms of leukaemogenesis.

My research interest is the impact of

leukaemia-associated fusion genes on the

normal processes of haematopoietic cell

proliferation, lineage differentiation, and

apoptosis. Of special interest is NPM-

MLF1, a fusion protein found in childhood

acute myelogenous leukaemia and myelodysplastic

syndromes. A mechanistic

profile of this oncogenic fusion protein

is pursued in in vivo approaches such as a

murine transplant model of retrovirally

transduced bone marrow, as well as a

transgenic approach.

Hitzler JK, Soares HD, Drolet DW, Inaba T,

O’Connel S, Rosenfeld MG, Morgan JI, Look AT.

Expression patterns of the hepatic leukemia factor

gene in the nervous system of developing and adult

mice. Brain Res 1999;820:1-11.

Hitzler JK, Witte DP, Jenkins NA, Copeland NG,

Gilbert DJ, Naeve CW, Look AT, Morris SW.

cDNA cloning, expression pattern, and chromosomal

localization of Mlf1, murine homologue of a gene

involved in myelodysplasia and acute myeloid

leukemia. Am J Pathol 1999;155:53-59.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Paediatric Consultants.

Research Institute

53


Research activities

Annual Report 2000-2001

54

Lisa Hornberger, Cardiovascular

Research: Investigation of

mechanisms responsible for cardiacmyocyte

proliferation and abnormal

fetal-heart development

My research is primarily focused on

elucidating the cellular and molecular

mechanisms that regulate cardiac-myocyte

proliferation, work initially sparked by

observations of human fetuses with and

without heart disease. Using an in vitro

culture system of human fetal ventricular

myocytes, I am investigating the role of

the extracellular matrix and integrin

receptors in epidermal growth factor and

insulin-like growth factor 2-dependent

cardiac-myocyte proliferation. My

laboratory is also assessing the effect of

a pulsatile mechanical stretch, used to

simulate ventricular preload, on cardiacmyocyte

proliferation. Ongoing clinical

investigations include assessment of the

role of maternal-plasma homocysteine

levels in the development of fetal-heart

disease and the elucidation of the

role of maternal autoantibodies in the

pathogenesis of fetal-heart block.

Maeno YV, Kamenir SA, Sinclair B, van der

Velde ME, Smallhorn JF, Hornberger LK. Prenatal

features of ductus arteriosus constriction and

restrictive foramen ovale in d-transposition of the

great arteries. Circulation 1999;99:1209-1214.

Kumar RK, Newburger JW, Gauvreau K, Kamenir

SA, Hornberger LK. Comparison of the outcome

when hypoplastic left heart syndrome and

transposition of the great arteries are diagnosed

prenatally versus when diagnosis of these two

conditions is made only postnatally. Am J Cardiol

1999;83:1649-1653.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Canadian Institutes of Health Research, Heart

and Stroke Foundation of Ontario, and March of

Dimes Birth Defects Foundation.

Andrew Howard, Population Health

Sciences: Preventing children’s

injuries from road traffic

Injuries from road traffic are the leading

cause of the death of children in most

developed countries, including Canada.

Children involved in motor vehicle crashes

can be injured because restraints were not

used, were misused, or were designed for

adults. Canada’s children have a high rate

of use of child restraints, but currently these

restraints are complex and prone to misuse.

My team seeks to understand how injuries

occur when children interact with safety

systems during accidents. This should lead

to better design of child restraints and

increased effective use rates.

Howard AW. Children, automobile restraints, and

injuries. Paediatr Child Health 2000;5(1): 24-30.

German A, Gardner WT, Howard AW. Mechanisms

of lap belt and air bag injuries in children. In:

Child occupant protection in motor vehicle crashes.

Bury St. Edmunds, UK: Professional Engineering

Publishing; 1999. p. 81-93.

Appointed to the Department of Surgery and

Health Administration at the University of Toronto.

External support provided by Ontario Neurotrauma

Foundation.

Lynne Howell, Structural Biology

& Biochemistry: Protein structure

and function

My colleagues and I are using x-ray

crystallographic techniques to study the

structure and function of a number of

different enzyme systems, including the

enzymes involved in the regulation of

biological methylation, methionine

recycling, N-glycan biosynthesis, and the

production of nitric oxide. The primary

goal of our research is to determine the

catalytic mechanism of the enzyme and to

exploit this information to design inhibitor

compounds for therapeutic use. We have

recently determined the structures of 5’

methylthioadenosine nucleosidase, yeast

α1,2-mannosidase, and argininosuccinate

synthetase. Site-directed mutagenesis and

other biophysical techniques are currently

being used to verify our proposed catalytic

mechanisms and to begin the process of

structure-based drug design.

Vallée F, Lipari F, Yip P, Sleno B, Herscovics A,

Howell PL. Crystal structure of a class I α1,2mannosidase

involved in N-glycan processing and

endoplasmic reticulum quality control. EMBO J

2000;19:581-588.

Howell PL, Blessing RH, Smith GD, Weeks CM.

Optimizing DREAR and SnB parameters for

determining Se-atom substructures. Acta Crystallogr

2000;D56:604-617.

Appointed to the Department of Biochemistry

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, National Institutes of Health, Natural

Sciences and Engineering Research Council

of Canada, and Tanabe Research Laboratories,

USA, Inc.

Jim Hu, Lung Biology: Gene

expression and lung gene therapy

My group is interested in gene expression

and lung gene therapy. One of our

research goals is to understand how gene

expression is regulated in airway epithelial

cells and to develop genetic tools to study

gene functions in the lung. We have

taken a novel approach to the development

of better expression cassettes for lung

gene therapy by using human regulatory

elements. Transgenic analysis in mice

showed that our cassettes can target efficient

transgene expression specifically to cells

where the CFTR gene is expressed. In

addition, my colleagues and I have been

characterizing human splicing factors that

play an essential role in pre-mRNA splicing.

Chow Y-H, Plumb J, Wen Y, Steer BM, Lu Z,

Buchwald M, Hu J. Targeting transgene expression

to airway epithelial submucosal glands, prominent

sites of human CFTR expression. Mol Ther

2000;2:359-367.

Koehler DR, Chow Y-H, Plumb J, Wen Y, Rafii B,

Belcastro R, Haardt M, Lukacs GL, Post M,

Tanswell AK, Hu J. A human epithelium-specific

vector optimized in rat pneumocytes for lung gene

therapy. Pediatr Res 2000;48:184-190.

Appointed to the Departments of Paediatrics,

Laboratory Medicine and Pathobiology, and the

Institute of Medical Science at the University

of Toronto. External support provided by Canadian

Cystic Fibrosis Foundation and Canadian Institutes

of Health Research.

Chi-chung Hui, Developmental

Biology: Hedgehog signalling in

development and cancer

The research in my laboratory focuses on

understanding the genetic control of

development and tumorigenesis. Using

mice as a model system, we have been

studying the role of normal and abnormal

hedgehog signalling in the nervous system

and skin. Our studies revealed that the

combinatorial activities of the two key

transducers of hedgehog signalling, Gli2

and Gli3, specify distinct ventral cell types

in the hindbrain and spinal cord. In the

embryonic epidermis, Gli2 is a regulator

of cell proliferation and its overexpression

in adult skin epidermis induces the

formation of basal cell carcinomas (the

most common human cancer). Currently,

we are pursuing biochemical and genetic

experiments to investigate the function of

various hedgehog-signalling components in

these two developmental systems.

Cohen DR, Cheng CW, Cheng SH, Hui C-c.

Expression of two novel mouse Iroquois homeobox

genes during neurogenesis. Mech Dev 2000;91:

317-321.

Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H,

Hui C-c, Dlugosz AA. Basal cell carcinomas in mice

overexpressing Gli2 in skin. Nat Genet 2000;24:

216-217.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, National Cancer Institute of

Canada, and Premier’s Research Excellence Award.

Shinya Ito, Integrative Biology:

Cellular drug transport

Drug movement across cell membranes

is a complex process that has significant

clinical implications. My research group

has been examining drug transport

mediated by P-glycoprotein, one of the

mechanisms of drug resistance in cancer

cells. Drug transport is also an essential

function in normal tissues such as breast,

kidney, intestine, and placenta. Focusing

on breast tissues, we are currently

characterizing drug-transport systems

in the human mammary gland to better

understand the safety of a mother’s

medications during breastfeeding.

In parallel, we have been studying

mechanisms of the well-known antibiotic

function of human milk; recently

we identified the presence of a naturally

occurring antibiotic peptide, called defensin,

in human mammary-gland epithelia.

Lala P, Ito S, Lingwood C. Retroviral transfection

of Madin-Darby canine kidney cells with human

MDR1 results in a major increase in globotriaosyl

ceramide and 10(5)- to 10(6)-fold increased cell

sensitivity to verocytotoxin. Role of P-glycoprotein

in glycolipid synthesis. J Biol Chem 2000;275:

6246-6251.

Tunzi CR, Harper PA, Bar-Oz B, Valore EV,

Semple JL, Watson-MacDonell J, Ganz T, Ito S.

β-defensin expression in human mammary gland

epithelia. Pediatr Res 2000;48:30-35.

Appointed to the Departments of Paediatrics and

Pharmacology, and the Faculty of Pharmacy at the

University of Toronto. External support provided by

Canadian Foundation for Women’s Health, Canadian

Institutes of Health Research, Eli Lilly Canada Inc.,

and PMAC Health Research Foundation.

Research Institute

55


Research activities

Annual Report 2000-2001

56

Zhengping Jia, Brain & Behaviour

Research: Molecular genetics of

synaptic plasticity and learning

and memory

Genetic factors contribute to behavioural

responses in both humans and rodents.

However, the genes that are responsible

for variations in normal behaviour, as well

as those for abnormal behaviour, ranging

from autism to learning disabilities are

largely unknown. My research has focused

on the identification of the genes that are

potentially important to the formation of

memory in mice. Specifically, my colleagues

and I are examining the molecular

mechanisms underlying hippocampal

long-term potentiation, a widely studied

cellular model for spatial learning in

rodents. Genetic manipulations, including

targeted-gene deletions and mutations,

allow us to investigate whether a gene

is important and how it controls the

formation of spatial memory in mice.

Rupes I, Jia ZP, Young PG. Ssp1 promotes actin

depolymerization and is involved in stress response

and new end take-off control in fission yeast. Mol

Biol Cell 1999;10:1495-1510.

Lei S, Jackson MF, Jia Z, Roder J, Bai D, Orser BA,

MacDonald JF. Cyclic GMP-dependent feedback

inhibition of AMPA receptors is independent of PKG.

Nat Neurosci 2000;3:559-565.

Appointed to Department of Physiology at the

University of Toronto. External support provided

by Canadian Institutes of Health Research.

Nicola Jones, Infection,

Immunity, Injury & Repair Research:

Pathogenesis and prevention of

Helicobacter infections

My research focuses on identifying the

mechanisms underlying the gastrointestinal

diseases associated with Helicobacter

infections, including both gastric cancers

and peptic ulcer disease in humans, and

inflammatory bowel diseases in animal

models. In addition, my colleagues and

I are characterizing the factors responsible

for successful immunization against

Helicobacter pylori infection to develop

effective vaccine strategies. We expect to

enhance the current understanding of how

these bacteria cause disease so that novel

therapies can be developed to prevent the

complications associated with infection.

Jones NL, Day AS, Jennings H, Sherman PM.

Helicobacter pylori induces gastric epithelial cell

apoptosis in association with increased Fas receptor

expression. Infect Immun 1999;67:4237-4242.

Jones NL, Islur A, Haq R, Mascarenhas M,

Karmali MA, Perdue MH, Zanke BW,

Sherman PM. Escherichia coli Shiga toxins induce

apoptosis in epithelial cells that is regulated by

the Bcl-2 family. Am J Physiol GI 2000;278:

G811-G819.

Appointed to the Departments of Paediatrics

and Physiology at the University of Toronto.

External support provided by American Digestive

Health Foundation, Canadian Digestive Disease

Foundation, and University of Toronto.

Debra Katzman, Population Health

Sciences: Medical complications in

adolescents with anorexia nervosa

My colleagues and I continue to investigate

the medical complications associated with

paediatric eating disorders. Our group is

exploring the structural brain abnormalities

found in adolescents with anorexia nervosa

(AN). With magnetic resonance imaging,

we found that adolescents with AN have

significant deficits in both grey-matter and

white-matter volumes. Grey-matter volume

deficits seem to be related to the degree

of weight loss and cortisol elevation. We

also demonstrated that weight-recovered

patients may have persisting deficits in

grey-matter volume. To date, very little

is known about the functional significance

of these brain abnormalities. We are

currently investigating the persistence of

both the brain abnormalities and cognitive

deficits and the association between them.

This research should help us understand

how these factors affect the potential for

recovery from this debilitating disorder.

Katzman DK, Golden NH, Neumark-Sztainer D,

Yager J, Strober M. From prevention to prognosis:

clinical research update on adolescent eating disorders.

Pediatr Res 2000;47:709-712.

Panagiotopoulos C, McCrindle BW, Hick K,

Katzman DK. Electrocardiographic correlates of

clinical status in adolescents with eating disorders.

Pediatrics 2000;105:1100-1105.

Appointed to the Departments of Paediatrics,

Human Development and Applied Psychology, the

Ontario Institute for Studies in Education, and

the Institute of Medical Science at the University

of Toronto. External support provided by Ontario

Mental Health Foundation.

Brian Kavanagh, Lung Biology:

Mechanical ventilation in critical

care medicine

Mechanical ventilation, or life support,

saves the lives of many critically ill patients

who are too ill to breathe adequately for

themselves. Setting the mechanical

ventilator so that the lungs are less

stretched reduces the incidence of death.

My laboratory has focused on two issues

in critical care medicine. First, we reported

that high levels of carbon dioxide, also

evident with reduced lung stretch, are

protective in laboratory models of critical

illness. We also showed that carbon dioxide

– generally considered a waste gas – can

be therapeutic for experimentally injured

lungs. Second, we demonstrated that

adverse ventilator settings can result in the

movement of harmful bacterial products

from the lung into the blood stream.

This may be important for patients with

lung infections who require life support.

Murphy DB, Cregg N, Tremblay L, Engelberts D,

Laffey JG, Slutsky AS, Romaschin A, Kavanagh BP.

Adverse ventilatory strategy causes pulmonary-tosystemic

translocation of endotoxin. Am J Respir Crit

Care Med 2000;162:27-33.

Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S,

Tanswell AK, Post M, Lindsay T, Kavanagh BP.

Therapeutic hypercapnia reduces pulmonary and

systemic injury in an in vivo lung reperfusion.

Am J Respir Crit Care Med 2000;162:2287-2294.

Appointed to the Departments of Critical Care

Medicine and Anaesthesia at the University

of Toronto. External support provided by the

Canadian Institutes of Health Research, Ontario

Thoracic Society, and The Physicians’ Services

Incorporated Foundation.

Frederick Keeley, Cardiovascular

Research: Regulation of synthesis

and assembly of elastin and elastinlike

proteins

Elastin is a major structural component

of arterial and other tissues. My laboratory

studies the regulation of the synthesis

and assembly of elastin, both in normal

development and in pathological situations

such as hypertension. We have shown that

the regulation of vascular elastin production

is complex, involving transcriptional rates,

the stability of mRNA, and the efficiency

of translation, secretion, and assembly.

We are investigating mechanisms

governing the stabilization-destabilization

and efficiency of the translation of elastin

mRNA, both in normal development

and in situations of elevated arterial-wall

stress. In addition, through investigations

of both elastin-like matrix proteins in lower

vertebrates and recombinantly expressed

domains of human elastin, we are studying

sequence, structure, and function

relationships in elastin, particularly the role

of hydrophobic domains in promoting

self-alignment and polymeric assembly.

Hew Y, Grzelczak Z, Lau C, Keeley FW.

Identification of a GA-rich sequence as a proteinbinding

site in the 3’UTR of chicken elastin

mRNA with a potential role in the developmental

regulation of elastin mRNA stability. J Biol Chem

2000;275:24857-24864.

Hew Y, Grzelczak A, Lau C, Keeley FW.

Identification of a large region of secondary structure

in the 3’-untranslated region of chicken

elastin mRNA with implications for the regulation

of mRNA stability. J Biol Chem 1999;274:

14415-14421.

Appointed to the Departments of Biochemistry,

and Laboratory Medicine and Pathobiology at

the University of Toronto. External support

provided by Canada Foundation for Innovation,

Canadian Institutes of Health Research, Heart

and Stroke Foundation of Ontario, Natural Sciences

and Engineering Research Council of Canada,

and Ontario Innovation Trust.

David Kenny, Population

Health Sciences: Dental Trauma

Research Group

The Dental Trauma Research Group,

of which I am a member, combines

clinical investigations of a range of dental

injuries with basic research into the

pathophysiology of periodontal ligament

injury and repair. As part of the Department

of Dentistry, we have conducted

protocol-based prospective traumamanagement

investigations since 1988.

We have published prospective outcome

studies of a number of specific dental

injuries. Our current focus is on the

potential of the amelogenin derivative

Emdogain to improve tooth survival and

initiate new therapies for avulsed and

severely intruded permanent teeth. This

is the first application of a biologically

active intervention for dental trauma.

Lin DG, Kenny DJ, Barrett EJ, Lekic P,

McCulloch CAG. Storage conditions of avulsed teeth

affect the phenotype of cultured human periodontal

ligament cells. J Periodont Res 2000;35:42-50.

Kenny DJ, Barrett EJ, Johnston DH, Sigal MJ,

Tenenbaum HC. Clinical management of avulsed

permanent incisors using Emdogain®: initial report

of an investigation. J Can Dent Assoc

2000;66(1):21.

Appointed to the Faculty of Dentistry at the

University of Toronto. External support provided

by The Hospital for Sick Children Foundation

and The Toronto Academy of Dentistry Crown

and Bridge Study Club.

Research Institute

57


Research activities

Annual Report 2000-2001

58

Antoine Khoury, Infection,

Immunity, Injury & Repair Research:

Prevention and treatment of

biomaterial-related infections

My research group has adopted two

approaches to the prevention and treatment

of biomaterial-related infections. The first

involves binding liposome-encapsulated

antibiotics to the surface of the implanted

device with a gelatin polyethylene glycol

system. We are currently carrying out

in vivo animal testing to confirm the

biocompatibility and efficacy of these

antimicrobial coatings. For our second

approach, we have developed an antimicrobial

composite polymer that releases

the antimicrobial agent in the presence of

an inflammatory process. Over the past

year, we used a rat peritonitis model,

challenged with pathogenic Pseudomonas

aeruginosa, to demonstrate the efficacy of

liposome-encapsulated antibiotics bound to

the surface of silicone coupons in the

prevention of their colonization.

Burrows LL, Khoury AE. Issues surrounding the

prevention and management of device-related

infections. World J Urol 1999;17:402-409.

DiTizio V, Karlgard C, Lilge L, Khoury AE,

Mittelman MW, DiCosmo F. Localized drug delivery

using crosslinked gelatin gels containing liposomes:

factors influencing liposome stability and drug

release. J Biomed Mater Res 2000;51:96-106.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Bayer Inc., Haemotronic, Inc., Materials and

Munufacturing Ontario, and The Kidney Foundation

of Canada.

Peter Kim, Infection, Immunity,

Injury & Repair Research: Immune

mechanisms of xenotransplantation

and developmental pathways in the

gastrointestinal tract

One potential solution to the current

shortage of potential donor organs is

the use of organs from species other

than human; however, this solution results

in significantly more severe rejection

reactions because of species differences. My

laboratory is interested in understanding

the cellular and molecular mechanisms of

immune responses to these xenografts. In

addition, as a paediatric general surgeon,

I operate on a number of children who are

born with congenital malformations of the

gastrointestinal system. As a consequence,

my laboratory is also interested in investigating

how the gastrointestinal tract is

formed normally, and what molecular and

genetic mechanisms are involved in

the congenital malformations of the

gastrointestinal tract.

Kimmel SG, Obatake M, Kushida M, Merguerian P,

Clarke ID, Kim PC. Murine xenogeneic immune

responses to the human testis: a presumed immuneprivileged

tissue. Transplantation 2000;69:1075-

1084.

Obataki M, Kushida M, Kimmel SG, Clarke ID,

Kim PC. T cells are necessary and critical for

xenograft rejection in new concordant cardiac

xenotransplant model. Transplantation

1999;67:1480-1484.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Heart and Stroke Foundation of Ontario.

Susan King, Population Health

Sciences: Research in perinatal and

paediatric human immunodeficiency

virus prevention and care, and

transfusion-associated infections

The national perinatal human

immunodeficiency virus (HIV) surveillance

program continues to provide important

information about the changing epidemiology

of perinatal HIV infection in

Canada. I, along with my colleagues from

the HIV/AIDS Program, have worked

with researchers from the Motherisk

Program to develop a national program to

study the effects of antiretroviral exposure

in pregnancy. Our research into HIV care

is multidisciplinary, integrating research

in the psychosocial and clinical aspects of

care. Our studies on infections from

transfusions are epidemiologic, providing

information such as estimates of the risk

of HIV infection from transfusions and the

incidence and consequences of hepatitis C

from transfusions in childhood.

King SM, Corey M, Major C, Poon A, Child R.

Safety of the Canadian blood supply in 1980-85:

using a paediatric cohort for risk assessment of human

immunodeficiency virus infection. Paediatr Perinat

Epidemiol 2001;15:68-73.

Salter Goldie RL, De Matteo D, Wells LM, Aykroyd

GR, King SM. Social planning in Canada for

families with HIV infection. Can J Pub Health

2000;91:353-356.

Appointed to the Departments of Paediatrics,

and Clinical Epidemiology and Health Care at the

University of Toronto. External support provided

by Agouron Pharmaceuticals, Inc., Biochem Pharma

and GlaxoWellcome, Health Canada, Merck Frosst

Canada Inc., and Ontario HIV Treatment Network.

Amira Klip, Cell Biology: Mechanism

of insulin regulation of glucose

uptake into muscle and fat cells

Insulin stimulation rapidly increases the

number and activity of glucose transporters

(GLUT4) at the muscle-fat cell surface.

Reductions in these responses characterize

the insulin resistance of diabetes. Using

single-cell assays with transfected cells, my

colleagues and I recently demonstrated that

1) insulin-induced actin remodelling collects

the insulin signals phosphatidylinositol

3-kinase (PI3K) and Akt together with

GLUT4 beneath the cell surface; 2) the

v-SNARE protein VAMP2, but not its

isoform VAMP3, is part of the insulin-sensitive

GLUT4 compartment; 3) the activity

of the GLUT4 glucose transporter is

regulated by p38 MAP kinase in cultured

cells and isolated muscle; and 4) the natural

cofactor lipoic acid increased glucose uptake

through PI3K/Akt and p38 MAPK,

supporting its potential use to treat

insulin resistance.

Khayat ZA, Tong P, Yaworsky K, Bloch RJ, Klip A.

Insulin-induced actin filament remodelling colocalizes

with phosphatidylinositol 3-kinase and GLUT4 in

L6 myotubes. J Cell Sci 2000;113:279-290.

Randhawa VK, Bilan PJ, Khayat ZA, Daneman N,

Liu Z, Ramlal T, Volchuk A, Peng XR, Coppola T,

Regazzi R, Trimble WS, Klip A. VAMP2, but not

cellubrevin, mediates insulin-dependent

incorporation of GLUT4 into the plasma membrane

of L6 myoblasts. Mol Biol Cell 2000;11:2403-2417.

Appointed to the Departments of Paediatrics,

Biochemistry, and Physiology at the University of

Toronto. External support provided by ASTA Medica

Aktiengesellschaft, Banting and Best Diabetes

Centre, Canadian Diabetes Association, Canadian

Institutes of Health Research, and Juvenile

Diabetes Foundation International.

Gideon Koren, Population Health

Sciences: Maternal-fetal and

paediatric pharmacology and

toxicology

My research focuses on understanding the

complex interactions between drugs, both

medicinal and illicit, and the developing

human being. These include the effects of

drugs taken by the mother on her unborn

baby, the role of the placenta in modulating

fetal damage, and the way babies and

children handle drugs. My colleagues and I

use research approaches ranging from those

of molecular and cell biology to wholebody

pharmacokinetic or dynamic

experiments and population studies. Our

strong collaboration with Dr Joanne Rovet

and the Department of Psychology allows

us to measure the neurobehavioural effects

of drugs on infants and children.

Hackman R, Kapur B, Koren G. Use of nicotine

patch by pregnant women. N Engl J Med

1999;341:1700.

Gallo M, Sarkar M, Waisze A, Pietrzak, Comas B,

Smith M, Jaeger TV, Einarson A, Koren G.

Pregnancy outcome following gestational exposure to

echinacea: a prospective controlled study. Arch Intern

Med 2000;160:3141-3143.

Appointed to the Departments of Paediatrics,

Pharmacology, Pharmacy, Medicine, and Medical

Genetics at the University of Toronto. External

support provided by Bristol-Myers Squibb Canada

Inc., Canadian Institutes of Health Research,

Duchesnay Inc, Novartis Farmaceutica S.A., Ontario

Veterinary Medical Association, The Hospital for

Sick Children Foundation, The Physicians’ Services

Incorporated Foundation, and Toronto Professional

Fire Fighter’s Association.

Michelle Letarte, Cancer & Blood

Research: Structure and function

of endoglin

Endoglin – discovered, cloned, and

sequenced in my laboratory – is a

glycoprotein expressed at high levels on

vascular endothelium. Endoglin interacts

with the signalling-receptor complex of

several growth factors of the transforming

growth factor-β superfamily. Endoglin

is the gene mutated in hereditary

haemorrhagic telangiectasia type 1

(HHT1), a dominant disorder associated

with often life-threatening arteriovenous

malformations. Reduced levels of endoglin

on endothelial cells are the underlying

cause of HHT1. Endoglin-deficient mice

die of abnormal vascular development at

mid-gestation. Only certain strains of mice

heterozygous for endoglin develop clinical

signs of HHT, suggesting a complex

disease influenced by modifier genes.

We are currently studying the vascular

and immune systems of mice with a single

endoglin copy and pursuing the analysis

of mutations in patients with HHT.

Bourdeau A, Dumont JD, Letarte M. A murine

model of hereditary hemorrhagic telangiectasia. J Clin

Invest 1999;104:1343-1351.

Cymerman U, Vera S, Pece-Barbara N, Bourdeau A,

White RI Jr, Dunn J, Letarte M. Identification

of hereditary hemorrhagic telangiectasia type 1 in

newborns by protein expression and mutation

analysis of endoglin. Pediatr Res 2000;47:24-35.

Appointed to the Departments of Immunology and

Medical Biophysics at the University of Toronto.

External support provided by Canadian Institutes of

Health Research, Heart and Stroke Foundation of

Ontario, March of Dimes Birth Defects Foundation,

The Hospital for Sick Children Foundation, and

SynX Pharma Inc.

Research Institute

59


Research activities

Annual Report 2000-2001

60

Susanna Lewis, Genetics & Genomic

Biology: Mechanism and fidelity

of antigen-receptor gene assembly

Rearrangement of DNA characterizes

cancers of the immune system, contributing

to both tumour development and

progression. Some aberrant alterations seen

in T and B cells are postulated to arise

through errors in a normal process called

V(D)J recombination. V(D)J recombination

is central to lymphocyte function, allowing

T and B cells to create new genes for

proteins that can bind foreign antigen.

Nevertheless, errors can occur in two

different phases of the V(D)J recombination

process: in the initial recognition of

DNA target sequences and later during

DNA rejoining. We are investigating

both kinds of error to better understand

the molecular mechanisms underlying

oncogenic alterations in lymphoid cells

and the conditions that might predispose

a cell to such mishaps.

Agard EA, Lewis SM. Postcleavage sequence

specificity in V(D)J recombination. Mol Cell Biol

2000;20:5032-5040.

Lewis SM. Palindromy is eliminated through a

structure-specific recombination process in rodent

cells. Nucleic Acids Res 1999;27:2521-2528.

Appointed to the Department of Medical Genetics

and Microbiology at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, National Cancer Institute of

Canada, Premier’s Research Excellence Award,

and University of Toronto.

Lorelei Lingard, Population Health

Sciences: Interprofessional

healthcare communication and

educational research

Interprofessional team communication –

how members of a health care team use

language to work collaboratively – is the

central focus of my research. My colleagues

and I also explore the influence of language

and reasoning on the development of

a novice’s professional identity. Using

predominantly qualitative methods, we

explore these issues in many clinical

domains, including surgery, psychiatry,

nursing, family medicine, internal

medicine, social work, and paediatrics.

For instance, one study documents

communicative tension and its effects on

team collaboration and trainee socialization

in the operating room. Another project

explores how third-year students in

paediatrics learn to present patient cases

to the medical team and how this learning

contributes to their evolving professional

attitudes towards patients and other health

care providers.

Lingard L, Haber RJ. What do we mean by

“relevance”? A clinical and rhetorical definition with

implications for teaching and learning the case

presentation format. Acad Med 1999;74(10

Suppl):S124-S127.

Haber R, Lingard L. Learning oral presentation

skills: a rhetorical analysis with pedagogical

and professional implications. J Gen Intern Med

2001;16:308-314.

Appointed to the Department of Paediatrics, the

Centre for Research in Education, and the

Department of Theory and Policy Studies at the

Ontario Institute for Studies in Education at the

University of Toronto. External support provided

by Association of Canadian Medical Colleges, Gold

Foundation for Humanism in Medicine, Medical

Council of Canada, Paediatric Consultants, Social

Sciences and Humanities Research Council

of Canada, and Lyle Roll Fund for the study of

Humane Medicine at the University of Michigan.

Clifford Lingwood, Infection,

Immunity, Injury & Repair Research:

Receptor function of glycolipids

My laboratory’s main research concerns

the role of globotriaosylceramide-Gb3 in

verotoxin (VT)-induced disease. The

lipid moiety of Gb3 and its membrane

environment affects its receptor function.

Different lipid isoforms of Gb3 may

mediate different intracellular VT

trafficking to affect pathology. We also

use VT to probe the role of Gb3 in CD19

and α2interferon receptor signal transduction

pathways. These proteins have

similar amino acid sequences to VT. Gb3 is upregulated on certain drug-resistant

tumours; we are investigating the role

of the Pgp drug pump in glycolipid

biosynthesis. Bacteria can express surface

heat-shock proteins, which then mediate

sulfogalactolipid (SGL) recognition. The

SGL-binding site is within the N-terminal

ATPase domain of hsp70. We devised new

water-soluble glycolipid mimics that inhibit

VT/Gb3 and hsp70/SGL binding, providing

new tools to study glycolipid biology.

Lala P, Ito S, Lingwood CA. Retroviral transfection

of madin-darby canine kidney cells with human

MDR1 results in a major increase in globotriaosylceramide

and 105- to 106-fold increased cell

sensitivity to verocytotoxin. J Biol Chem

2000;275:6246-6251.

Mamelak D, Lingwood C. The ATPase domain of

hsp70 possesses a unique binding specificity for 3’sulfogalactolipids.

J Biol Chem 2001;276:449-456.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, and Biochemistry

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, Crohn’s & Colitis Foundation of Canada,

National Cancer Institute of Canada, Select

Therapeutics (Canada) Inc., and The Hospital

for Sick Children Foundation.

Howard Lipshitz, Developmental

Biology: Molecular genetic control

of development

My research is focused on understanding

how embryonic cells are instructed to adopt

distinct developmental fates, ultimately

specifying a complex three-dimensional

organism. My colleagues and I use the fruit

fly Drosophila as a model to study maternal

contributions to early development,

particularly maternal transcripts and the

control of their stability in the early

embryo; intracellular mRNA localization

mechanisms that establish informational

asymmetry in cells; the developmental

functions of mRNA localization; the

genetic control of morphogenetic cellshape

changes and movements during

development; and genetic control of

epithelial integrity during organogenesis.

Wilk R, Reed BH, Tepass U, Lipshitz HD. The

hindsight gene is required for epithelial maintenance

and differentiation of the tracheal system

in Drosophila. Dev Biol 2000;219:183-196.

Lipshitz HD, Smibert CA. Mechanisms of RNA

localization and translational regulation. Curr

Opin Genet Dev 2000;10:476-488.

Appointed to the Departments of Medical

Genetics and Microbiology, Molecular and Medical

Genetics, and the Institute of Medical Science at

the University of Toronto. External support

provided by Canadian Institutes of Health Research

and National Cancer Institute of Canada.

William Logan, Brain & Behaviour

Research: Functional organization

of normal and abnormal human

brains during development

Three questions are investigated in my

research: 1) where do neurological

functions reside in the developing brain?

2) how are they organized? and 3) how

can this be influenced? My colleagues

and I use functional magnetic resonance

imaging (MRI), a noninvasive technique

that provides an image of the brain, to

visualize the areas of the brain that are

involved during a sensory, motor, or

cognitive task. With MRI, we study normal

young subjects, subjects with developmental

brain abnormalities or long-standing brain

damage, and those with acquired brain

injury to determine the patterns of

organization, reorganization, and recovery

of function in the brain. The long-term

goal is to understand the functional

organization of the brain so that specific

interventions to improve the neurological

and cognitive function of patients with

impairments can be developed.

Benson RR, FitzGerald DB, LeSueur LL,

Kennedy DN, Kwong KK, Buchbinder BR,

Davis TL, Weisskoff RM, Talavage TM, Logan WJ,

Cosgrove GR, Belliveau JW, Rosen BR. Language

dominance determined by whole brain functional

MRI in patients with brain lesions. Neurology

1999;52:798-809.

Logan WJ. Functional magnetic resonance imaging

in children. Semin Pediatr Neurol 1999;6:78-86.

Appointed to the Departments of Paediatrics

and Medicine at the University of Toronto. External

support provided by Paediatric Consultants and

The Hospital for Sick Children Foundation.

Maureen Lovett, Brain & Behaviour

Research: Rehabilitation of reading

and language disorders in children

and adolescents

My research program is devoted to the

study of specific language-learning disorders

of childhood, with a focus on developmental

reading disabilities. Ongoing

projects involve treatment-outcome studies

and evaluate the efficacy of different forms

of remediation for children and adolescents

with severe reading disabilities. Current

work evaluates ways of combining effective

treatment components to maximize

children’s treatment response. In collaboration

with my colleagues at the hospital and

in the United States, I have begun multisite

intervention studies to evaluate the effectiveness

of 1) three different treatments

to remediate the core speech-based deficits

of children with severe reading disabilities,

2) a combination of stimulant medication

and specific remedial treatments for

children with both attention-deficit hyperactivity

disorder and reading disabilities,

and 3) early intervention for children at

significant risk for reading disorders. New

projects focus on the genetics of reading

disabilities and community applications

of research-based intervention programs

in elementary and secondary schools.

Lovett MW, Lacerenza L, Borden SL, Frijters JC,

Steinbach KA, De Palma M. Components of effective

remediation for developmental reading disability:

combining phonological and strategy-based

instruction to improve outcomes. J Educ Psychol

2000;92:263-283.

Lovett MW, Lacerenza L, Borden SB. Putting

struggling readers on the PHAST track: a program

to integrate phonological and strategy-based remedial

reading instruction and maximize outcomes. J Learn

Disabil 2000;33:458-476.

Appointed to the Departments of Psychology and

Paediatrics at the University of Toronto, and the

graduate faculties of Psychology at the University

of Waterloo, the University of Guelph, and York

University. External support provided by Canadian

Institutes of Health Research and National

Institutes of Health.

Research Institute

61


Research activities

Annual Report 2000-2001

62

Gergely Lukacs, Cell Biology: CFTR

trafficking and DNA metabolism

The subcellular localization of the cystic

fibrosis transmembrane conductance

regulator (CFTR) is critical for

transepithelial water and salt transport.

My research team’s objective is to elucidate

the cellular mechanisms responsible for

the normal targeting of CFTR to the

apical membrane and for misprocessing

mutant proteins. Further studies will

examine the role of secretion, endocytosis,

and degradation in the regulation of

CFTR density at the cell surface. Other

experiments aim at uncovering those events

(metabolism, translocation, and kinetic and

diffusional mobility) that determine the

intracellular fate of plasmid DNA during

gene transfer. To elucidate the regulation

of the chromosomal DNA degradation,

the activation mechanism of the caspaseactivated

apoptotic nuclease is studied.

Sharma M, Benharouga M, Hu W, Lukacs GL.

Conformational and temperature-sensitive stability

defects of the DF508 cystic fibrosis transmembrane

conductance regulator in post-endoplasmic reticulum

compartments. J Biol Chem 2001;276:8942-8950.

Lechardeur D, Drzymala L, Sharma M, Zylka D,

Kinach R, Pacia J, Hicks C, Usmani N, Rommens

JM, Lukacs GL. Determinants of the nuclear

localization of the heterodimeric DNA fragmentation

factor (ICAD/CAD). J Cell Biol 2000;150:321-334.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, Surgery, and the

Institute of Medical Science at the University

of Toronto. External support provided by Canadian

Institutes of Health Research, Canadian

Cystic Fibrosis Foundation, and National Institutes

of Health.

Colin Macarthur, Population Health

Sciences: Paediatric Outcomes

Research Team

As director of the Paediatric Outcomes

Research Team, I apply epidemiological

methods to better understand (and

ultimately improve) the diagnosis,

management, and outcomes of common

childhood conditions. Our patient-based

research is conducted in the hospital

wards, ambulatory clinics, and community

practices. My research has focused on

the role of Helicobacter pylori in recurrent

abdominal pain and also on the

prevention of childhood injury. Injury is

the leading cause of childhood death and

disability. My research aims to quantify

the burden, identify aetiologic factors

for injury, and critically evaluate injury

prevention strategies.

Macarthur C, Hu X, Wesson DE, Parkin PC.

Risk factors for severe injuries associated with falls

from playground equipment. Accid Anal Prev

2000;32:377-382.

Macarthur C, Saunders N, Feldman W, Ipp M,

Winders-Lee P, Roberts S, Best L, Sherman P,

Pencharz P, Veldhuyzen van Zanten SV.

Helicobacter pylori and childhood recurrent

abdominal pain: community-based case-control

study. B Med J 1999;319:822-823.

Appointed to the Departments of Paediatrics

and Health Administration at the University of

Toronto. External support provided by Canadian

Institutes of Health Research.

Christopher Macgowan, Integrative

Biology: Fast measurements of

cardiovascular function with magnetic

resonance imaging

My colleagues and I use magnetic

resonance imaging for the noninvasive

study of cardiovascular function. Our

work includes the development of fast

measurements of heart motion and blood

flow, which are relevant to congenital

heart disease and the development of the

cardiovascular system. From the deformation

of the heart and vessel walls, we can

calculate the mechanical properties of these

elastic organs. Mechanical abnormalities

can affect circulation and the workload of

the heart. Analysis of three-dimensional

blood-flow patterns also provides information

about the blood pressure, shearing

forces between the blood and wall, and

mechanical properties of the vessel.

Collectively, these measurements may help

us assess patients before and after therapy,

and improve our understanding of the

progression of diseases.

Macgowan CK, Wood ML. Motion measurements

from individual MR signals using volume

localization. J Magn Reson Imaging 1999;9:

670-678.

Macgowan CK, Wood ML. Fast measurements of

the motion and velocity spectrum of blood using MR

tagging. Magn Reson Med 2001;45:461-469.

Don Mahuran, Structural Biology &

Biochemistry: Lysosomal storage

diseases and proteomics

My laboratory’s specific genetic and

biochemical work continues to correlate

the mutations in any of three genes that

result in the variable clinical presentations

associated with GM2 gangliosidoses

(i.e., Tay-Sachs and Sandhoff disease, or

the AB-variant forms). A more general

approach to understanding these and

related diseases involves first mapping

(two-dimensional gel electrophoresis)

and identifying (microsequencing with

mass spectrometry) all soluble, associated,

or integral membrane proteins contained

in the lysosomes of normal cells. Next, the

protein components of lysosomes from

patient cells must be compared. Missing

proteins can define the cause of the disease,

or increased or decreased levels of groups

of proteins can indicate lysosomal involvement

in a disease process. We will also use

these techniques to determine whether

lysosomal proteins are organized into

complexes called Metabolons.

Bagshaw RD, Callahan JW, Mahuran DJ. Desalting

of in-gel-digested protein sample with mini-C18

columns for matrix-assisted laser desorption

ionization time of flight peptide mass fingerprinting.

Anal Biochem 2000;284:432-435.

Hou Y, Vocadlo D, Withers S, Mahuran D.

Role of βArg211 in the active site of human

β-hexosaminidase B. Biochemistry 2000;39:

6219-6227.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, and Medicine at the

University of Toronto. External support provided by

Canadian Institutes of Health Research.

David Malkin, Cancer & Blood

Research: Genetics of familial cancer

Cancer is often familial. The Li-Fraumeni

syndrome defines an association of breast

cancer, sarcomas, and other neoplasms in

young family members. Inherited mutations

of the p53 tumour-suppressor gene predispose

many members of these families to

cancer. My laboratory has used molecular

and functional assays to characterize the

p53 alterations in patients with multiple

primary cancers and in children with

osteosarcomas, rhabdomyosarcoma, adrenocortical

carcinomas, or brain tumours. We

are examining the role of other cell-cycle

control genes in the predisposition to

cancer in children, as well as the secondary

genetic and epigenetic events, including

viral infection, that cooperate with underlying

defects in p53 to cause cancer to

develop. The Cancer Genetics Program

in the Division of Oncology has been

developed to define new familial cancer

syndromes and initiate studies of novel

cancer-predisposing genes.

Portwine C, Lees J, Verselis S, Li FP, Malkin D.

Absence of germline p16 alterations in Li-Fraumeni

syndrome patients who lack detectable germline p53

mutations. J Med Genet 2000;37:E13.

Brown LTR, Sexsmith E, Malkin D. Identification

of a novel PTEN intronic deletion in Li-Fraumeni

syndrome and its effect on RNA processing. Cancer

Genet Cytogenet 2000;123:61-68.

Appointed to the Departments of Paediatrics and

Medical Biophysics, and the Institute of Medical

Science at the University of Toronto. External

support provided by Cancer Care Ontario, Leukemia

Research Fund of Canada, National Cancer Institute

of Canada, Pediatric Oncology Group of Ontario,

The Hospital for Sick Children Foundation, and

University of Toronto.

Katharina Manassis, Brain &

Behaviour Research: Understanding

and treating childhood anxiety

disorders and associated conditions

Childhood anxiety disorders are common

and frequently disabling conditions.

Unfortunately, the causes of anxiety in

children are poorly understood and

treatments are not well researched. My

program aims to elucidate the cognitive,

familial, and genetic mechanisms

underlying childhood anxiety disorders

and associated conditions, and to test the

effectiveness of cognitive, behavioural,

and medical treatments for these disorders.

Currently, my colleagues and I study

cognitive mechanisms in children with

both anxiety and attention problems,

and genetic mechanisms in children

with anxiety disorders. We compare

individual- and group-based cognitive

behaviour therapies for anxious children

and their families.

Manassis K, Tannock R, Barbosa J. Dichotic listening

and response inhibition in children with comorbid

anxiety disorders and ADHD. J Am Acad Child

Adolesc Psychiatry 2000;39:1152-1159.

Mendlowitz S, Manassis K, Bradley S, Scapillato D,

Miezitis S, Shaw BF. Cognitive-behavioral group

treatments in childhood anxiety disorders: the role of

parental involvement. J Am Acad Child Adolesc

Psychiatry 1999;38:1223-1229.

Appointed to the Department of Psychiatry at the

University of Toronto. External support provided by

Ontario Mental Health Foundation and Psychiatry

Endowment Fund.

Research Institute

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Research activities

Annual Report 2000-2001

64

Patricia Massicotte, Population

Health Sciences: Paediatric

thrombophilia

In a cross-sectional study of warfarin, an

internationally recommended anticoagulant

for the long-term treatment and prevention

of thrombosis, my research team found

that most of the children receiving warfarin

for more than 1 year had significantly

decreased bone density compared with

normal children of the same age. To more

clearly delineate this relationship, we are

undertaking a study that controls for the

factors affecting the bone density of

children taking long-term warfarin. We

are also evaluating the safety and efficacy

of low molecular-weight heparin

(LMWH), which does not decrease bone

density long-term in animals. The results

of our preliminary prospective study of a

large cohort of children (infants to teens)

receiving LMWH were very promising.

Multicentre randomized clinical trials

comparing LMWH and standard care

for the treatment and prophylaxis of

thrombosis are currently ongoing.

Dix D, Andrew M, Marzinotto V, Charpentier K,

Bridge S, Monagle P, deVeber G, Leaker M, Chan A,

Massicotte MP. The use of low molecular weight

heparin in paediatric patients: a prospective cohort

study. J Pediatr 2000;136:439-445.

Massicotte MP. Low-molecular-weight heparin

therapy in children. J Pediatr Hematol Oncol

2000;22:98-99.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Heart and Stroke Foundation of Ontario.

Anne Matlow, Population Health

Sciences: Understanding paediatric

nosocomial infections

Patients admitted to the hospital are at

risk of developing infections, termed

nosocomial infections, that can complicate

and extend their hospital stay. Because

many of these infections are preventable,

it is important to understand which

patients get infected and the circumstances

and scenarios that precede these infections.

My research focuses primarily on the

clinical and molecular epidemiology of

nosocomial infections in children,

particularly those children hospitalized

in intensive care units.

Matlow A, Kovach D, Wray R, Streitenberger L,

Goldman C, Freeman R. Application of pulsed-field

gel electrophoresis to the epidemiological investigation

of clusters of infection in a pediatric institution –

a two-year review. Can J Infect Control 2000;

Winter:133-136.

Friedman S, Shah V, Ohlsson A, Matlow A.

Neonatal Escherichia coli infections: concerns

regarding resistance to current therapy. Acta Paediatr

2000;89:686-689.

Appointed to the Departments of Paediatrics, and

Laboratory Medicine and Pathobiology at the

University of Toronto. External support provided

by Paediatric Consultants.

Brian McCrindle, Cardiovascular

Research: Early markers of

atherosclerosis in high-risk children

Children with inherited disorders of

cholesterol metabolism are often at greatly

increased risk of having heart attacks or

strokes as adults. Children who have had

the inflammatory condition Kawasaki

disease may also have damage to the

arteries and be at increased risk of early

atherosclerosis. The Vascular Disease

Prevention Clinic, in which I practise,

is committed to preventing and detecting

early atherosclerosis in children with these

conditions. We have developed ultrasound

methods to assess the thickness and

abnormalities of the function of the arteries

as early markers of atherosclerosis, and are

currently studying factors and treatments

that may affect this disease.

Silva AAE, Maeno Y, Hashmi A, Smallhorn JF,

Silverman ED, McCrindle BW. Cardiovascular risk

factors after Kawasaki disease: a case-control study.

J Pediatr 2001;138:400-405.

Han RK, Sinclair B, Newman A, Silverman ED,

Taylor GW, Walsh P, McCrindle BW. Recognition

and management of Kawasaki disease. Can Med

Assoc J 2000;162:807-812.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Heart and Stroke Foundation of Ontario, Pfizer

Canada Inc., and The Physicians’ Services

Incorporated Foundation.

Jane McGlade, Cell Biology:

Regulation of signal-transduction

pathways controlling cell

proliferation, differentiation, and

fate determination

My research is directed towards

understanding the regulation of signaltransduction

pathways that control normal

embryonic development and cellular

function, and are relevant to disease states

such as cancer. Recently, my colleagues and

I have focused specifically on a family of

intracellular adapter molecules that can

function to integrate, localize, and downregulate

signal-transduction cascades. My

laboratory has identified new adapters such

as GADS, which function in antigenreceptor

signalling, and NUMB and LNX,

which regulate the activity of transmembrane

receptors that determine cell fate

during development. Currently, work in

my laboratory focuses on the functional

characterization of these new molecules,

in addition to continuing studies on

the SHC adapter and its role in tyrosine

kinase-mediated signal transduction.

Liu SK, Smith CA, Arnold R, Kiefer F, McGlade

CJ. The adaptor protein GADS (Grb2-related

adaptor downstream to Shc) is implicated in coupling

hemopoietic progenitor kinase-1 to the activated

TCR. J Immunol 2000;165:1417-1426.

Yoder J, Pham C, Iizuka YM, Kanagawa O, Liu SK,

McGlade CJ, Cheng A. Requirement for the SLP-76

adaptor GADS in T cell development. Science

2001;291:1987-1991.

Appointed to the Department of Medical Biophysics

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, National Cancer Institute of Canada,

Premier’s Research Excellence Award, The

Cancer Research Society Inc., and The Hospital

for Sick Children Foundation.

Roderick McInnes, Developmental

Biology: The molecular and cellular

basis of eye development and of

inherited neuronal degenerations

My research team is examining two

fundamental biological and medical

problems. First, we wish to understand

the molecular and cellular events that lead

to the development of the mammalian eye,

as a model system for neurodevelopment.

We have used multiple strategies to identify

genes critical to eye development, including

the homeobox gene CHX10, which is

associated with human-eye malformations.

Our current goal is to investigate a more

difficult problem – how this gene, and

others like it, regulate eye formation. Our

discovery of retinal stem cells will facilitate

this work. Second, we wish to elucidate the

molecular and biochemical basis of

inherited neurological degenerations,

particularly retinal degenerations. We have

identified two photoreceptor-degeneration

genes (CRX and ROM1) and have

discovered that a common principle

underlies many, if not most, neurodegenerations,

including Parkinson and

Huntington disease.

Clarke G, Collins RA, Leavitt BR, Andrews DF,

Hayden MR, Lumsden CJ, McInnes RR.

A one-hit model of cell death in inherited neuronal

degeneration. Nature 2000;406:195-199.

Ferda Percin E, Ploder LA, Yu JJ, Arici K,

Horsford DJ, Rutherford A, Bapat B, Cox DW,

Duncan AMV, Kalnins VI, Kocak-Altintas A,

Sowden JC, Traboulsi E, Sarfarazi M, McInnes RR.

Human microphthalmia associated with mutations

in the retinal homeobox gene CHX10. Nat Genet

2000;25:397-401.

Holder of the Anne and Max Tanenbaum Chair in

Molecular Medicine at The Hospital for Sick Children.

Appointed to the Departments of Paediatrics, and

Molecular and Medical Genetics, and the Institute

of Medical Science at the University of Toronto.

External support provided by Canadian Genetic

Disease Network, Canadian Institutes of Health

Research, Howard Hughes Medical Institute, Macular

Vision Research Foundation (USA), University

Medical Discoveries Inc., and University of Toronto.

Stephen Meyn, Genetics & Genomic

Biology: Chromosome-instability

syndromes and cellular defences

against DNA damage

My laboratory studies how human cells

respond to DNA damage. Our work

focuses on the chromosome-instability

syndromes, a group of cancer-prone

inherited diseases in which normal defences

against genetic damage are disrupted

(e.g., ataxia-telangiectasia, Werner

syndrome, Fanconi anaemia, and Bloom

syndrome). Our current research includes

the following: 1) the use of fluorescence

microscopy to study the role chromosomeinstability-syndrome

proteins play in

meiosis, a form of cell division that requires

cells to deliberately break their DNA;

2) investigation of the link between

genomic instability and aging, by studying

the involvement of chromosome instability

syndrome proteins in maintenance of

chromosome ends (telomeres); and

3) the use of laser microablation techniques

and fluorescently tagged proteins to

directly study the association of DNA

repair proteins with damaged DNA in

living cells.

Fritz E, Friedl AA, Zwacka RM, Eckardt-Schupp F,

Meyn MS. The yeast TEL1 gene partially substitutes

for human ATM in suppressing hyperrecombination,

radiation-induced apoptosis and telomere shortening

in A-T cells. Mol Biol Cell 2000;11:2605-2616.

Garcia-Higuera I, Taniguchi T, Ganesan S,

Meyn MS, Timmers C, Hejna J, Grompe M,

D’Andrea AD. Interaction of the Fanconi anemia

proteins and BRCA1 in a common pathway.

Mol Cell 2001;7:249-262.

Appointed to the Departments of Molecular and

Medical Genetics, and Paediatrics at the University

of Toronto. External support provided by Ataxia-

Telangiectasia Medical Research Foundation.

Research Institute

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Research activities

Annual Report 2000-2001

66

Berge Minassian, Genetics &

Genomic Biology: Genetics of rare

epilepsies and muscular dystrophies

The paediatric neurologist, more often

than not, is helpless in the face of disease

afflicting his or her patients. For this

reason, I spend 80% of my time in the

laboratory to help further the knowledge

of these diseases and design better

treatments. I work in partnership with

Dr. Stephen Scherer on an inherited

epilepsy (Lafora disease), which starts in

adolescence and ends with the death of

the youth. We identified the gene for this

disorder and are unravelling, step-by-step,

the function of its protein product, and are

investigating treatment protocols. I also

work on a rare form of muscular dystrophy

(X-linked myopathy with excessive autophagy),

the gene for which we are close

to identifying.

Minassian BA, Ianzano L, Meloche M, Andermann

E, Rouleau GA, Delgado-Escueta AV, Scherer SW.

Mutation spectrum and predicted function of laforin

in Lafora’s progressive myoclonus epilepsy. Neurology

2000;55:341-346.

Auranen M, Villanova M, Muntoni F, Fardeau M,

Scherer SW, Kalino H, Minassian BA. X-linked

vacuolar myopathies: two separate loci and refined

genetic mapping. Ann Neurol 2000;47:666-669.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Bloorview Childrens Hospital Foundation and The

Hospital for Sick Children Foundation.

Lesley Mitchell, Population Health

Sciences: Randomized controlled

trials in paediatrics

For children, the safety and efficacy of

certain types of drugs such as blood

thinners are extrapolated from the findings

of adult studies. However, for many

biological reasons, the findings of adult

clinical trials are not always applicable

to children. Paediatric clinical trials pose

unique challenges, both in design and

implementation. Commonly, these studies

require collaboration with many paediatric

hospitals around the world. To date, some

clinical trials for children have not been

done because of their complexity. My

research involves designing and

implementing these large clinical trials for

children. Primarily, I am investigating

blood-thinning drugs that prevent blood

clots. These clinical studies assess both

standard available drugs and new bloodthinning

drugs.

Streif W, Andrew M, Marzinotto V, Massicote P,

Chan AK, Julian J, Mitchell L. Analysis of warfarin

therapy in paediatric patients: a prospective cohort

study of 319 patients. Blood 1999;94:3007-3014.

Male C, Mitchell L, Julian J, Vegh P, Joshua P,

Adams M, David M, Andrew ME. Acquired

activated protein C resistance is associated with lupus

anticoagulants and thrombotic events in paediatric

patients with systemic lupus erythematosus. Blood

2001;97:844-849.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Canadian Institutes of Health Research and Heart

and Stroke Foundation of Ontario.

David Nicholas, Population Health

Sciences: Psychosocial issues and

paediatric chronic illness

My research program focuses on

psychosocial issues related to paediatric

chronic illness. Substantive areas of

interest include technology, group work

and support, quality of life, family

member roles in adaptation, lived

experiences of fathers and mothers of

children with chronic illness, and effectiveness

of psychosocial interventions.

Griffiths AM, Nicholas DB, Smith C, Munk M,

Stephens D, Durno C, Sherman PM. Development

of a quality-of-life index for pediatric inflammatory

bowel disease: dealing with differences related to

age and IBD type. J Pediatr Gastroenterol Nutr

1999;28:S46-S52.

Nicholas DB. Meanings of maternal caregiving:

children with end stage renal disease. Qual Health

Res 1999;9:468-478.

Appointed to the Faculty of Social Work at the

University of Toronto. External support provided by

Brainchild, Canadian Lung Association, KidsAction

Research, Ontario Lung Association, Social Sciences

and Humanities Research Council, The Kidney

Foundation of Canada, The STARBRIGHT

Foundation, University of Toronto, and William T.

Grant Foundation.

Michael Noseworthy, Integrative

Biology: Assessment of

microvasculature with magnetic

resonance techniques

My research focuses on the development

and application of magnetic resonance

imaging (MRI) methods and image

processing algorithms for the assessment

of tissue architecture and function. With

this safe imaging technology, which does

not rely on harmful x-rays, I am studying

tissue microvasculature, viability, and brain

activation patterns in health and disease.

More specifically, my work involves the

assessment of normal and pathologic brain

regions with functional MRI. Additionally,

I am using dynamic MRI and magnetic

resonance oximetry in the investigation

of paediatric cancer blood flow (perfusion)

and tumour oxygenation, both of which

may be useful for understanding disease

progression and therapeutic efficacy.

Noseworthy MD, Sussman MS, Haider M,

Baruchel S. Dynamic liver MRI with a motion

correction algorithm. ISMRM 2001;9:2240.

Noseworthy MD, Kim JK, Stainsby JA, Stanisz GJ,

Wright GA. Tracking oxygen effects on MR signal

in blood and skeletal muscle during hyperoxia

exposure. J. Magn Reson Imaging 1999;9:814-820.

Appointed to the Department of Medical Biophysics

at the University of Toronto.

Hugh O’Brodovich, Lung Biology:

Na transport in the developing lung

– implications for disease

My colleagues and I continue our interest

in the mechanisms responsible for the

genesis and recovery from lung diseases

that are characterized by fluid-filled

airspaces. Our experiments show that

epithelial active Na + transport by Na +

channels is required to clear the fluid that

normally fills the lung at birth and that

the cells lining the distal regions of the

lungs play a role in this Na + transport.

The biochemical, electrophysiologic, and

signal-transduction characteristics of these

cells’ Na + channels differ in several ways

from nonlung epithelia. Our ongoing

studies are investigating the effect of lung

maturity and hormones on the pre- and

posttranslational regulation of the epithelial

Na + channel, and Na and fluid transport

by the healthy and oedematous lung.

Smith DE, Otulakowski G, Yeger H, Post M,

Cutz E, O’Brodovich H. Epithelial Na + channel

(ENaC) expression in the developing normal

and abnormal human perinatal lung. Am J Respir

Crit Care Med 2000;161:1322-13310.

Pitkänen OM, Smith D, O’Brodovich H,

Otulakowski G. Expression of alpha-, beta-, and

gamma-hENaC mRNA in the human nasal,

bronchial, and distal lung epithelium. Am J Respir

Crit Care Med 2001;163:273-276.

Holder of the R.S. McLaughlin Foundation Chair in

Paediatrics at The Hospital for Sick Children.

Appointed to the Departments of Paediatrics and

Physiology at the University of Toronto. External

support provided by Canadian Institutes of Health

Research, Heart and Stroke Foundation of Ontario,

Ontario Thoracic Society, and The Hospital for Sick

Children Foundation.

Deborah O’Connor, Integrative

Biology: Strategies to improve

the nutritional status of women

and infants

My research program is focused on two

broad areas of maternal and infant

nutrition. First, my colleagues and I are

interested in understanding the factors

that affect the folate status of women

of reproductive age and of infants and

young children. In particular, we are

investigating the impact of bacterial

biosynthesis of vitamins in the colon

on folate status and possible methods

of manipulating bacterial biosynthesis

to improve the nutrition and health of

humans. Second, we are studying the

impact of early feeding, specifically the

use of human-milk fortifiers and novel

food ingredients, on the growth and

development of premature infants.

Barrett Reis B, Hall RT, Schanler RJ, Berseth CL,

Chan G, Ernst JA, Lemons J, Adamkin D,

Baggs G, O’Connor D. Enhanced growth of preterm

infants fed a new powdered human milk fortifier:

a randomized, controlled trial. Pediatrics

2000;106:581-588.

Goodwin RA, Buchholz A, McKim MK, Stuart B,

O’Connor DL. Caregiving arrangement and

nutrition: good news with some reservations. Can

J Public Health 1999;90:45-51.

Appointed to the Department of Nutritional

Sciences at the University of Toronto. External

support provided by Abbott Laboratories, Limited.

Research Institute

67


Research activities

Annual Report 2000-2001

68

Anne Opavsky, Infection,

Immunity, Injury & Repair

Research: Host susceptibility to

coxsackieviral infection

My research focuses on identifying the

key factors that determine the response

of a host to infections with group B

coxsackieviruses. These viruses are

responsible for a wide range of disease

phenotypes, including severe disease

affecting the heart, liver, pancreas, and

brain. My colleagues and I are

characterizing the role viral receptors

and downstream intracellular signalling

molecules play in coxsackieviral disease.

A better understanding of factors that

determine susceptibility and resistance

to viral infection will enable us to

effectively target preventative strategies

and establish new approaches to therapy.

Opavsky MA, Penninger J, Aitken K, Wen W-H,

Dawood F, Mak T, Liu P. Susceptibility to

myocarditis is dependent on the response of αβ T

lymphocytes to coxsackieviral infection. Circ Res

1999;85:551-558.

Liu P, Aitken K, Kong Y-Y, Opavsky MA, Martino

T, Dawood F, Wen W-H, Kozieradzki I, Bachmaier

K, Straus D, Mak TW, Penninger JM. The tyrosine

kinase p56lck is essential in coxsackievirus B3mediated

heart disease. Nat Med 2000;6:429-434.

Appointed to the Department of Paediatrics at the

University of Toronto.

Cecil Pace-Asciak, Integrative

Biology: Hepoxilin analogues –

Potential as new drugs

The hepoxilins, which my colleagues and

I discovered several years ago, are

hydroxyepoxide metabolites of arachidonic

acid that are relatively unstable in the

body. Using chemical synthesis, we have

prepared stable analogues that mimic

the in vivo actions of the unstable natural

parent compounds, namely, the inhibition

of inflammatory disease, the release

of insulin into the circulation, the insulinindependent

decrease of glucose in the

circulation, and the inhibition of the

onset of diabetes. Additional studies have

indicated that one of the chemical

analogues is a potent inhibitor of platelet

aggregation with potential utility in the

treatment of cardiovascular disease. We

have identified a specific binding protein

responsible for these actions and are

currently investigating its peptide structure.

Pace-Asciak CR, Reynaud D, Demin P, Nigam SN.

The hepoxilins: a review. In: Nigam SN,

Pace-Asciak CR, editors. Lipoxygenases and their

metabolites. New York: Plenum Press; 1999.

p. 123-132.

Pace-Asciak CR, Demin PM, Estrada M, Liu G-Y.

Hepoxilins raise circulating insulin levels in vivo.

FEBS Lett 1999;461:165-168.

Appointed to the Department of Pharmacology at

the University of Toronto. External support

provided by Canadian Institutes of Health Research

and University Medical Discoveries Inc.

Cho Pang, Integrative Biology:

Ischaemia and radiotherapy-induced

injury in skin and muscle: Mechanism

and pharmacologic intervention

Two areas of surgical research are being

pursued in my laboratory. In the first, we

investigate the pathogenic mechanism of

skin ischaemia and radiotherapy-induced

impaired wound healing in skin-flap

surgery, with special emphasis on the role

of vasoactive substances and growth factors

released by the blood, inflammatory, and

endothelial cells. In the second area of

research, we investigate the cellular

mechanism of ischaemic preconditioning

of skeletal muscle against ischaemia and

reperfusion injury in autogenous muscle

transplantation and replantation of

amputated limbs. In particular, we focus

on adenosine-PKC-KATP channel-linked

events. These areas of research could result

in the identification of therapeutic agents

for optimal prophylactic treatment against

ischaemia and radiotherapy-induced injury

in skin and muscle.

Hopper RA, Forrest CR, Xu H, Zhong A, He W,

Rutka J, Neligan P, Pang CY. Role and mechanism

of PKC in ischemic preconditioning of pig skeletal

muscle against infarction. Am J Physiol 2000;R666-

R676.

Zhang J, Lipa JE, Black CE, Huang N, Neligan

PC, Ling FT, Levine RH, Semple JL, Pang CY.

Pharmacological characterization of vasomotor

activity of human musculocutaneous perforator artery

and vein. J Appl Physiol 2000;89:2268-2275.

Appointed to the Departments of Surgery and

Physiology, and the Institute of Medical Science

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, Smokeless Tobacco Research Council,

Inc., and The Hospital for Sick Children

Foundation.

Blake Papsin, Brain & Behaviour

Research: Auditory system

development after cochlear

implantation

Research in my laboratory is directed at

determining how the auditory system

develops after cochlear implantation in

young children. We examine the auditory

system using electrophysiologic

measurements and compare the time

course of development with the known

rates of development for persons with

normal hearing. In addition, we analyze

speech and language outcomes to

identify the optimal time for cochlear

implantation and possible factors that

might predict superior performance.

Papsin BC, Gysin C, Picton N, Nedzelski J,

Harrison RV. Speech perception outcome measures

in prelingually deaf children up to four years after

cochlear implantation. Ann Otol Rhinol Laryngol

(Suppl) 2000;185:38-42.

Gordon KA, Daya H, Harrison RV, Papsin BC.

Factors contributing to limited open-set speech

perception in children who use a cochlear implant.

Int J Pediatr Otorhinolaryngol 2000;56:101-111.

Appointed to the Department of Otolaryngology

at the University of Toronto. External support

provided by The Physicians’ Services Incorporated

Foundation and The Hospital for Sick Children

Foundation.

Patricia Parkin, Population Health

Sciences: The Paediatric Outcomes

Research Team

As a member of the Paediatric Outcomes

Research Team, I research common

paediatric problems and children’s health

status using epidemiological methods.

In our study of the predictors of healthrelated

quality of life (HRQL) for children

and adolescents with spina bifida, we

found that parental hopefulness was more

strongly associated with HRQL than

neonatal or current physical deficits. In our

study of playground injuries, we found that

the risk of severe injury is twofold for falls

from heights above 150 cm compared with

those from lower heights.

Kirpalani HM, Parkin PC, Willan AR,

Fehlings DL, Rosenbaum PL, King D, Van Nie AJ.

Quality of life in spina bifida: importance of

parental hope. Arch Dis Child 2000;83:293-297.

Macarthur C, Hu X, Wesson DE, Parkin PC.

Risk factors for severe injuries associated with falls

from playground equipment. Accid Anal Prev

2000;32:377-382.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Paediatric Consultants.

Christopher Pearson, Genetics

& Genomic Biology: Mechanisms

of disease-associated trinucleotide

repeat mutations

My research concerns the molecular

mechanisms of genetic mutations involving

trinucleotide repeat sequences. The

mutation responsible for at least 14 serious

human genetic diseases has been traced

to the genetic variation in the lengths of

specific (CAG)n, (CTG)n, (CGG)n, or

(GAA)n trinucleotide repeats in DNA.

Many of the diseases associated with this

form of mutation affect the neurological

or neuromuscular systems, for example,

myotonic dystrophy, Huntington disease,

and fragile X mental retardation. To

prevent or treat these diseases at the DNA

level, it is imperative that we understand

the molecular details of the mechanism of

instability. My laboratory’s research focuses

on the contribution of DNA replication

and DNA repair to the genetic instability

of trinucleotide repeats.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Fragile X Research Foundation

of Canada, Muscular Dystrophy Association (USA),

and University of Toronto.

Research Institute

69


Research activities

Annual Report 2000-2001

70

Paul Pencharz, Integrative Biology:

Amino acid and energy requirements

throughout life and disease

My primary research interest is the amino

acid requirements of infants, children,

and adults, and the way they are altered

by disease. My colleagues and I use stable

isotopes to measure amino acids

requirements and have modified techniques

so that they are suitable for use in children

5 to 6 years old. This has allowed us to

determine the tyrosine needs of children

with phenylketonuria. About 40 per cent

of the neonates at our hospital require

intravenous feeding (TPN). We have

established a piglet TPN model, and

have shown that TPN, which bypasses

the gut, alters the requirements for amino

acids. Parallel studies conducted in

neonates are confirming our findings in

the piglets. Our current work on energy

requirements is focused on the effect

of spinal-cord injury on resting and total

daily energy expenditure.

Bross R, Ball RO, Clarke JTR, Pencharz PB.

Tyrosine requirements in children with classical

PKU determined by indicator amino acid oxidation.

Am J Physiol 2000;278:E195-E201.

Brunton JA, Ball RO, Pencharz PB. Current total

parenteral nutrition solutions for the neonate

are inadequate. Curr Opin Clin Nutr Metab Care

2000;3:299-304.

Appointed to the Departments of Paediatrics and

Nutritional Sciences at the University of Toronto.

External support provided by Canadian Cystic

Fibrosis Foundation, Canadian Institutes of Health

Research, Ontario Neurotrauma Foundation,

Pediatric Oncology Group of Ontario, and The

Hospital for Sick Children Foundation.

Max Perlman, Population Health

Sciences: Studies of adverse brain

outcomes of newborn infants

I conduct observational studies on the

causes, diagnosis, and prognosis of neonatal

illnesses. Observational studies can be used

to identify interventions associated with

good or with adverse outcomes and to build

predictive models. To assess quality of care,

risk adjustment techniques are used to

compare more objectively the outcomes of

infants treated in different hospitals or

during different eras. My current research

focuses on the failure of haematological and

acid-base measures to diagnose birth

asphyxia, clinical indicators of the diving reflex

(a brain-protecting reflex) in the fetus

with asphyxia; causes and prognosis of

renal-vein thrombosis; and the accuracy

of different statistical methods for

predicting outcomes. I also study issues

related to the ethical conduct of research.

Klinger G, Chin CN, Beyene J, Perlman M.

Predicting the outcome of neonatal bacterial

meningitis. Pediatrics 2000;106:477-482.

Perlman M. Ethical issues in “observational

research”. Paediatr Child Health 2000;5:89-90.

Appointed to the Department of Paediatrics

at the University of Toronto. External support

provided by Paediatric Consultants and The

Physicians Services Incorporated Foundation.

Martin Petric, Infection, Immunity,

Injury & Repair Research: Biology

of gastroenteritis viruses and other

viral agents

Gastroenteritis viruses are important

pathogens, particularly in a paediatric

setting. My laboratory has been

investigating the basic biology and

epidemiology of these agents, and the

development of diagnostic assays for

them. We have demonstrated that

toroviruses are important agents of

gastroenteritis in our setting, both as

human and animal pathogens. Currently,

the viral genomes are being further

characterized and tests are being developed

for the diagnosis of these viruses.

Other viruses being investigated include

the Coxsackie group B viruses (CVBs).

Findings include the sequence of the

genome of CVB-6 and defining the

receptors for CVB-3 and other Coxsackie

viruses. My laboratory is also involved

in studies of the Epstein-Barr virus

and its role in posttransplant lymphoproliferative

disease.

Duckmanton L, Tellier R, Richardson C, Petric M.

The novel hemagglutinin-esterase genes of human

torovirus and Breda virus. Virus Res 1999;64:

137-149.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, and Medical

Genetics and Microbiology at the University

of Toronto. External support provided by

Canadian Institutes of Health Research.

Régis Pomès, Structural Biology &

Biochemistry: Theoretical studies

of biomolecular structure, function,

and dynamics

Understanding the basic physical principles

that govern the fold and function of

proteins is paramount to the prediction

and rationalization of the biological activity

of newly discovered proteins. To this end,

my colleagues and I use computer

simulations to study biological systems

at the molecular level. Currently, the

laboratory is engaged in three main

directions of research. 1) We are studying

the dynamic events involved in the folding

and proper function of soluble proteins.

2) We are developing novel computational

methods for the prediction of proteinligand

binding affinities to help in the

discovery of new therapeutic agents

(rational drug design). 3) We are studying

the molecular mechanism of proton

transport across biological membranes,

a process that is essential to life itself

(respiration, metabolism).

Pomës R, Eisenmesser E, Post CB, Roux B.

Calculating excess chemical potentials using dynamic

simulations in the fourth dimension. J Chem Phys

1999;111:3387-3395.

Pomës R. Theoretical studies of the Grotthuss

mechanism in biological proton wires. Isr J Chem

1999;39:387-395.

Holder of a Tier II Canada Research Chair.

Appointed to the Department of Biochemistry at

the University of Toronto. External support

provided by Canadian Institutes of Health

Research and National Institutes of Health.

Martin Post, Lung Biology:

Developmental lung morphogenesis

The lung originates from the distinct tissue

layers epithelium and mesoderm. Mutual

interactions of these tissue layers are

essential for lung organogenesis. The

morphogenetic signals regulating lung

organogenesis include cell-extracellular

matrix interactions, direct cell-cell contact

mediated by cell-membrane components,

and soluble factors. My colleagues and

I use in vitro and in vivo approaches to

identify factors involved in the complex

process of lung formation. Another area

of research is related to ventilation-induced

injury. Intermittent mechanical strain,

simulating fetal-breathing movements,

stimulates fetal-cell proliferation, whereas

continuous strain injures the fetal cells.

We investigate signalling pathways

initiating and mediating the strain effect,

as well as transcriptional activation in

fetal cells subjected to aberrant mechanical

strain and hyperoxia. Finally, we are

investigating the importance of a hypoxic

environment for early placentation and

pulmonary morphogenesis.

Keijzer R, Liu J, Deimling J, Tibboel D, Post M.

Dual-hit hypothesis explains pulmonary hypoplasia

in the nitrofen model of congenital diaphragmatic

hernia. Am J Pathol 2000;156:1299-1306.

Caniggia I, Mostachfi H, Winter J, Gassmann M,

Lye SJ, Kuliszewski M, Post M. Hypoxia inducible

factor-1 mediates the biological effects of oxygen on

human trophoblast differentiation through TGFb3.

J Clin Invest 2000;105:577-587.

Holder of a Tier I Canada Research Chair.

Appointed to the Departments of Paediatrics,

Physiology, and Laboratory Medicine and

Pathobiology at the University of Toronto.

External support provided by Canadian Institutes

of Health Research and The Hospital for Sick

Children Foundation.

Marlene Rabinovitch, Cardiovascular

Research: The cellular and molecular

biology of vascular disease

Targeting endogenous vascular elastase

(EVE), which is associated with progressive

pulmonary vascular disease, induces

regression of even advanced pulmonary

hypertension in experimental animals.

Elastase inhibitors also decrease the

incidence of experimental posttransplant

coronary artery disease, reduce the

myocardial necrosis associated with

rejection, and prevent the sequelae of

murine myocarditis and myocardial

infarction. My research group used gene

transfer with decoy RNA to sequester a

protein that increases fibronectin mRNA

translation to re-engineer the ductus

arteriosus to prevent closure. We have also

created transgenic mice that overexpress

the elastase inhibitor elafin, and have used

gene transfer with recombinant elafin to

prevent restenosis and the obstruction

of vein grafts in rabbits. We have also

discovered a novel hypertension gene.

Zaidi SHE, You X-M, Ciura S. O’Blenes S,

Husain M, Rabinovitch M. Supressed smooth muscle

proliferation and inflammatory cell invasion after

arterial injury in elafin-overexpressing mice. J Clin

Invest 2000;105:1687-1695.

Cowan KN, Heilbut A, Humpl T, Lam C, Ito S,

Rabinovitch M. Complete reversal of fatal

pulmonary hypertension in rats by a serine elastase

inhibitor. Nat Med. 2000;6:698-702.

Holder of the Heart and Stroke Foundation of

Ontario/Robert Freedom Chair in Cardiovascular

Science at The Hospital for Sick Children.

Appointed to the Departments of Paediatrics,

and Laboratory Medicine and Pathobiology at

the University of Toronto. External support

provided by Canadian Institutes of Health

Research, Heart and Stroke Foundation of Ontario,

The Hospital for Sick Children Foundation, and

University of Toronto.

Research Institute

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Research activities

Annual Report 2000-2001

72

Margaret Rand, Integrative

Biology: Blood-platelet function

and dysfunction

Platelets are important in haemostasis,

aggregating to arrest the flow of blood

from injured blood vessels; platelets

can also form arterial thrombi in blood

vessels diseased with atherosclerosis

and cause heart attacks and strokes.

My colleagues and I are studying the

mechanisms involved in platelet function

and dysfunction. In one line of research,

Drs Victor Blanchette, Manuel Carcao,

Gabrielle deVeber, and I are investigating

hereditary and acquired disorders of platelet

function that can result in bleeding or

thrombosis. As well, studies of the reduced

functions of stored platelets transfused

into patients with low platelet counts are

underway. We are also examining effectors

of platelet function in vivo, including

those involved in platelet procoagulant

activity and in the clearance of platelets

from the circulation.

Rand ML, Packham MA, Taylor DM, Yeo EL,

Gemmell CH, Patil S, Lam SC-T. The fibrinogen γ

chain dodecapeptide inhibits agonist-induced

aggregation of rabbit platelets and fibrinogen binding

to rabbit glycoprotein IIb-IIIa. Thromb Haemost

1999;82:1680-1686.

Dean JA, Blanchette VS, Carcao MD, Stain AM,

Sparling CR, Siekmann J, Turecek PL, Lillicrap D,

Rand ML. von Willebrand disease in a pediatricbased

population. Comparison of type 1 diagnostic

criteria and use of the PFA-100®‚ and a von

Willebrand factor/collagen-binding assay. Thromb

Haemost 2000;84:401-409.

Appointed to the Departments of Biochemistry,

and Laboratory Medicine and Pathobiology at

the University of Toronto. External support

provided by Canadian Blood Services, Dade Behring

Inc., Heart and Stroke Foundation of Ontario,

and Medsep Corporation (Pall Medical).

Peter Ray, Genetics & Genomic

Biology: Functional analysis of

dystrophin, the DMD gene product

My research focuses on the molecular

analysis of Duchenne muscular dystrophy,

a common neuromuscular disease

characterized by progressive muscle

degeneration that results in death around

the age of 20 years. The DMD gene

uses seven promoters and alternative

splicing to generate a large family of

proteins (dystrophins) with significant

structural and functional differences.

My colleagues and I are currently using

genetic and biochemical methods to

study the interactions of each of these

protein isoforms with other membrane

proteins. We are constructing mutant

mouse models for a more detailed genetic

study of the functions of these isoforms.

We hope the analysis of DMD isoforms

will provide a clearer definition of the

function of this family of proteins and

lead to rational therapies for this disease.

Howard PL, Dally GY, Ditta SD, Austin RC,

Worton RG, Klamut HJ, Ray PN. Dystrophin

isoforms Dp71 and Dp427 have distinct roles in

myogenic cells. Muscle Nerve 1999;22:16-27.

Austin RC, Morris GE, Howard PL, Klamut HJ,

Ray PN. Expression and synthesis of spliced variants

of Dp71 in adult human brain. Neuromuscul Disord

2000;10:187-193.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canada Foundation

for Innovation, Canadian Institutes of Health

Research, Ontario Research and Development

Challenge Fund, and The Hospital for Sick Children

Foundation.

Stan Read, Infection, Immunity,

Injury & Repair Research:

Perinatal human immunodeficiency

virus infection

My research focuses on several aspects

of perinatal human immunodeficiency

virus (HIV): its transmission and the

prevention of its transmission, and its

natural history in HIV-infected children.

Using dried blood spots, my colleagues

and I are comparing DNA polymerase

chain reaction (PCR) with reverse

transcription-PCR for the detection of

vertical infection. In the Bahamas, all

HIV-infected pregnant women are offered

zidovudine to prevent HIV transmission,

which reduces it by about 60%. In a

randomized placebo-control trial, we are

currently studying whether the addition

of nevirapine to this regimen further

reduces HIV transmission. Other areas

of investigation include changes in HIV

V3-loop sequences with clinical progression,

HIV-resistance mutations in

children on antiretroviral therapy, changes

in intracellular cytokines in HIV infection,

and changes in CD4 and CD8 naive

and memory cells in children on antiretroviral

therapy.

Dallas S, Read SE, King S, Koren G, Bendayan R.

Pharmacokinetic interaction between zidovudine and

trimethoprim/sulphamethoxazole in HIV-1 infected

children. Can J Infect Dis 2000;11:254-258.

Allen U, Conway B, Forbes J, King S, Lapointe N,

Marshall C, Gilmour J, Moore D, Stephens D,

Wells G, Cassol S, Read S. Zidovudine resistance and

associated factors among HIV-infected Canadian

children. Can J Infect Dis 2001;12:113-115.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Abbott Laboratories, Limited, Canadian Blood

Services, Exergen Corporation, Ministry of Health

and Long-Term Care, and The Hospital for Sick

Children Foundation.

Susan Richardson, Infection,

Immunity, Injury & Repair Research:

Fungal infections in the immunocompromised

child

While the incidence of serious fungal

infections in immunocompromised children

is increasing, common pathogenic fungi are

becoming increasingly resistant to current

antifungal antibiotics. An important area

of my research has been antifungal

susceptibility testing – its methods, the

correlation of laboratory results with

clinical outcome in human infections, and

the study of trends in the susceptibility

of common fungal pathogens to antifungal

agents in serious invasive infections in

Toronto hospitals. In addition, I am leading

a multicentre Canadian study that is

investigating the epidemiology, risk factors,

and outcome of neonatal candidiasis.

Clinical trials of new antifungal agents

and the rapid diagnosis of fungal infections

are two other areas of active research.

Friedman S, Richardson SE, Jacobs SE, O’Brien K.

Systemic Candida infection in extremely low birth

weight infants – short-term morbidity and long-term

neurodevelopmental outcome. Pediatr Infect Dis J

2000;19:499-504.

Cowen LE, Sirjusingh C, Summerbell RC,

Walmsley S, Richardson S, Kohn LM, Anderson JB.

Multilocus genotypes and DNA fingerprints do not

predict variation in azole resistance among clinical

isolates of Candida albicans. Antimicrob Agents

Chemother 1999;43:2930-2938.

Appointed to the Department of Pathobiology and

Laboratory Medicine at the University of Toronto.

External support provided by Covance Canada, Inc.

and Pfizer Canada Inc.

Eve Roberts, Metabolism Research:

Childhood liver diseases caused by

excess metals

The focus of my laboratory’s research is

childhood liver diseases in which a metal,

such as copper or iron, damages liver

cells. Although copper is essential for the

normal function of numerous critically

important enzymes in humans, it is toxic

in excess. Likewise, iron is normally found

in the liver of newborns, but in some

conditions, hepatic iron deposition is

increased and liver damage occurs. We are

especially interested in the mechanism of

liver damage in Wilson disease (copper

overload) caused by mutations in a P-type

ATPase (ATP7B, also known as WND)

and perinatal haemochromatosis (iron

overload) associated with neonatal liver

failure. By developing pertinent animal

and in vitro cell culture models for these

disorders, we expect to find novel and

innovative therapies.

Wilson DC, Phillips MJ, Cox DW, Roberts EA.

Severe hepatic Wilson’s disease in preschool-aged

children. J Pediatr 2000;137:719-722.

Khalil M, Shariat-Panahi A, Tootle R, Ryder T,

McCloskey P, Roberts E, Hodgson H, Selden C.

Human hepatocyte cells lines as cohesive spheroid

colonies in alginate markedly upregulates both

synthetic and detoxificatory liver function. J Hepatol

2001;34:68-77.

Appointed to the Departments of Paediatrics,

Medicine, and Pharmacology at the University of

Toronto. External support provided by American

Association for the Study of Liver Diseases,

Canadian Institutes of Health Research, and

Schering Canada Inc.

Brian Robinson, Metabolism

Research: Genetic origin of

mitochondrial diseases

Canadian children are born every year with

unusual disorders of energy metabolism

that are difficult to recognize and diagnose,

and result in a multitude of problems

affecting the heart, kidney, liver, and brain.

My colleagues and I study two mitochondrial

diseases, the pyruvate carboxylase

deficiency that is prevalent in First Nations

children of Ojibwa, Cree, and Micmac

origin, and the hepatic form of cytochrome

oxidase deficiency, which occurs only in

the Saguenay-Lac Saint-Jean region of

Québec. We also study children from all

over the world who have similar diseases.

We have defined the genetic defects in

the DNA of both the nucleus and the

mitochondria that are responsible for

these disorders. We also assess whether the

pathogenesis of the disease process is a lack

of energy or the accumulation of abnormal

toxic metabolites.

Seyda A, Newbold RF, Hudson TJ, Verner A,

MacKay N, Winter S, Feigenbaum A, Malaney S,

Gonzalez-Halphen D, Cuthbert AP, Robinson BH.

A novel syndrome affecting multiple mitochondrial

functions, located by microcell-mediated transfer to

chromosome 2p14 - 2p13. Am J Hum Genet

2001;68:386-396.

Raha S, Merante F, Shoubridge E, Myint AT, Tein

I, Benson L, Johns T, Robinson BH. Repopulation of

rho0 cells with mitochondria from a patient with a

mitochondrial DNA point mutation in tRNAGly results in respiratory chain dysfunction. Hum Mutat

1999;13:245-254.

Holder of a Tier I Canada Research Chair.

Appointed to the Departments of Biochemistry and

Paediatrics at the University of Toronto. External

support provided by Canadian Genetic Diseases

Network, Canadian Institutes of Health Research,

Heart and Stroke Foundation of Ontario, The

Hospital for Sick Children Foundation, and United

Mitochondrial Disease Foundation.

Research Institute

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Research activities

Annual Report 2000-2001

74

Chaim Roifman, Infection,

Immunity, Injury & Repair Research:

Molecular basis of immunodeficiency

and lymphoid malignancy

The focus of research in my laboratory

continues to include the identification and

functional characterization of novel signaltransduction

elements in normal lymphoid

tissues and their role in immunodeficiency,

leukaemia, and lymphoma. This work has

recently led to the cloning and sequencing

of a T-cell-specific tyrosine phosphatase,

Lyp, and the characterization of the role

of Eph receptors in lymphoid-cell

development and function. In addition,

we have recently identified several novel

immunodeficiency syndromes, including

IL-Rα and IL-7Rα deficiencies. We have

also established a murine model of purine

nucleoside phosphorylase deficiency, which

provides insight into the pathogenesis of

this disease and will serve as an ideal model

for gene therapy.

Cohen S, Dadi H, Shaoul E, Sharfe N,

Roifman CM. Cloning and characterization of a

lymphoid-specific, inducible human protein tyrosine

phosphatase, Lyp. Blood 1999;93:2013-2024.

Arpaia E, Benveniste P, Di Cristofano A, Gu Y,

Dalal I, Kelly S, Hershfield M, Pandolfi PP,

Roifman CM, Cohen A. Mitochondrial basis for

immune-deficiency. Evidence from purine nucleoside

phosphorylase-deficient mice. J Exp Med

2000;191:2197-2208.

Holder of the Donald and Audrey Campbell Chair

in Immunology at The Hospital for Sick Children.

Appointed to the Departments of Paediatrics,

Medicine, and Immunology at the University of

Toronto. External support provided by Aventis

Behring Canada Inc., Bayer Inc., Canadian Genetic

Diseases Network, Canadian Institutes of Health

Research, Lotte & John Hecht Memorial

Foundation, LymphoSign Inc., National Cancer

Institute of Canada, and The Hospital for Sick

Children Foundation.

Johanna Rommens, Genetics &

Genomic Biology: Mechanisms of

genetic disease

My laboratory is interested in the

understanding the basic defects of

genetic diseases and the consequences of

mutated proteins. We are examining the

biogenesis of the protein product of the

cystic fibrosis transmembrane conductance

regulator to understand how mutant

proteins are recognized and whether they

lead to specific consequences in cells or

in the clinical presentation of cystic fibrosis.

The goals of our studies of Shwachman-

Diamond syndrome, a recessive disorder

associated with exocrine pancreatic

insufficiency, haematological dysfunction,

and bone abnormalities, are to identify

the affected gene and to understand both

the development and pathobiology of

the disease.

Van Oene M, Lukacs GL, Rommens JM. Cystic

fibrosis mutations lead to carboxyl-terminal

fragments that highlight an early biogenesis step

of the cystic fibrosis transmembrane conductance

regulator. J Biol Chem 2000;275:19577-19584.

Ginzberg H, Shin J, Ellis L, Goobie S, Morrison J,

Corey M, Durie PR, Rommens JM. Segregation

analysis in Shwachman-Diamond syndrome:

evidence for recessive inheritance. Am J Hum Genet

2000;66:1413-1416.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canadian Genetic

Diseases Network, Canadian Institutes of Health

Research, National Institutes of Health, Premier’s

Research Excellence Award, Shwachman Diamond

Syndrome Canada Inc., and The Hospital for Sick

Children Foundation.

Norman Rosenblum, Developmental

Biology: Morphogenesis of the

mammalian kidney

The goal of research in my laboratory is

to define the molecular mechanisms that

underlie the formation of the normal and

malformed kidney. In our recent work, we

identified the cellular and molecular mechanisms

by which bone morphogenetic

protein (BMP) 2 and BMP7 control the

formation of branched tubules, a process

that is fundamental to renal organogenesis.

In addition, we defined the embryologic

basis for renal dysplasia in a glypican-3deficient

mouse model of Simpson-Golabi-

Behmel syndrome and implicated

glypican-3 in BMP signalling. Our current

work focuses on defining the actions of

BMPs and their signalling partners in

in vivo models of renal development, and

elucidating their contribution to congenital

renal disease.

Piscione TD, Phan T, Rosenblum ND. BMP7

controls collecting tubule cell proliferation and

apoptosis via Smad1-dependent and -independent

pathways. Am J Physiol Renal Physiol

2001;280:F19-F33.

Grisaru S, Cano-Gauci D, Tee J, Filmus J,

Rosenblum ND. Glypican-3 modulates BMPand

FGF-mediated effects during renal branching

morphogenesis. Dev Biol 2001;231:31-46.

Appointed to the Departments of Paediatrics and

Physiology, and the Institute of Medical Science

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, The Kidney Foundation of Canada, and

The Physicians’ Services Incorporated Foundation.

Daniela Rotin, Cell Biology: Role of

tyrosine phosphatases in mammalian

development and the function and

targets of the ubiquitin ligase Nedd4

Work in my laboratory focuses on two

major projects. The first project is the

role of LAR family protein tyrosine

phosphatases (PTPs), particularly PTPsigma

in signalling and its development. We

knocked out the gene for PTPsigma

in mice, which resulted in severe neuroendocrine

and neuronal defects. We are

currently studying both the biochemical

and biological functions of this PTP. In

our second project, we demonstrated that

Nedd4 binds by its WW domains to the

PY motifs (xPPxY) of the epithelial Na +

channel (ENaC), which are mutated in

patients with Liddle syndrome, a hereditary

form of hypertension. We also showed that

ENaC stability and function are regulated

by ubiquitination and by Nedd4. Recently,

we identified the novel Nedd4 substrate

CNrasGEF, which activates Ras in

response to cAMP. We are currently

characterizing its function and regulation.

Wallace MJ, Batt J, Fladd CA, Henderson JT,

Skarnes W, Rotin D. Neuronal defects and posterior

pituitary hypoplasia in mice lacking the receptor

tyrosine phosphatase PTPσ. Nat Genet

1999;21:334-338.

Pham N, Cheglakov I, Koch CA, de Hoog CL,

Moran MF, Rotin D. The guanine nucleotide

exchange factor CNrasGEF activates Ras in response

to cAMP and cGMP. Curr Biol 2000;10:555-558.

Appointed to the Department of Biochemistry

at the University of Toronto. External support

provided by Canadian Cystic Fibrosis Foundation,

Canadian Institutes of Health Research, Human

Frontier Science Program, and Premier’s Research

Excellence Award.

Joanne Rovet, Brain & Behaviour

Research: Neurocognitive sequelae

of paediatric and maternal thyroid

disease, and fetal teratogen exposure

My laboratory is studying how insufficient

thyroid hormone during pregnancy or

after birth and intrauterine exposure to

teratogenic substances such as alcohol and

organic solvents affects infant and child

neurodevelopment. We are also investigating

the role of the thyroid hormone

in memory and attention in children with

congenital hypothyroidism and attentiondeficit

hyperactivity disorder, and the

effect of severe hypoglycaemia on neural

substrates of memory. In collaboration

with Motherisk, we also study infants

exposed in utero to alcohol, cocaine,

organic solvents, anticonvulsants, and

antidepressants. We recently developed

a new electrophysiological laboratory in

collaboration with Ophthalmology to assess

basic visual functions in infants such as

visual acuity and contrast sensitivity. Our

ultimate goal is to identify at a functional

level the neural manifestations of factors

that perturb early brain development.

Ishaik G, Asztalos E, Perlman K, Newton S, Frisk V,

Rovet J. Hypothyroxinemia of prematurity and

infant neurodevelopment: a pilot study. J Dev Behav

Pediatr 2000;21:172-179.

Rovet J, Ehrlich R. The psychoeducational characteristics

of children with early-treated congenital

hypothyroidism. Pediatrics 2000;105:515-522.

Appointed to the Departments of Paediatrics and

Psychology at the University of Toronto. External

support provided by Banting and Best Diabetes

Centre, Canadian Institutes of Health Research,

Eli Lilly Canada Inc., and March of Dimes Birth

Defects Foundation.

James Rutka, Brain & Behaviour

Research: Cytoskeletal and cell-cycle

control of human astrocytomas

The astrocytoma is the most common

malignant brain tumour arising from

within the central nervous system. This

disease is invariably fatal, despite treatment

with any form of conventional therapy.

Over the years, my laboratory has focused

on two areas of research related to astrocytoma:

cytoskeletal-matrix interactions

and cell-cycle control mechanisms. In

the first, we have been studying the role

of the astrocyte-specific intermediatefilament

glial fibrillary acidic protein in

astrocytoma morphology and signalling

pathways. In the second, we have been

determining the effects of inducing cyclindependent

kinase inhibitors on human

astrocytoma tumorigenicity. We believe

that the knowledge obtained from these

studies may be translated, in a relatively

short time, into novel therapeutic strategies

with both scientific and clinical merit.

Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG,

Drake JM, Rutka JT. Familial posterior fossa

brain tumors of infancy secondary to germline

mutation of the hSNF5 gene. Am J Hum Genet

2000;66:1403-1406.

Tsugu A, Sakai K, Dirks PB, Jung S, Weksberg R,

Fei Y-L, Mondal S, Ivanchuk S, Ackerley C, Hamel

PA, Rutka JT. Expression of p57(KIP2) potently

blocks the growth of human astrocytomas and induces

cell senescence. Am J Pathol 2000;157:919-932.

Appointed to the Department of Surgery at the

University of Toronto. External support provided

by Brainchild, Canadian Institutes of Health

Research, National Brain Tumor Foundation,

National Cancer Institute of Canada, and The

Physicians’ Services Incorporated Foundation.

Research Institute

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Research activities

Annual Report 2000-2001

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Michael Salter, Brain & Behaviour

Research: Cellular and molecular

mechanisms of sensory transmission

in the spinal dorsal horn

Neurones in the dorsal horn of the spinal

cord integrate signals from various inputs

and send projections to areas of the brain

involved in processing, analyzing, and

responding to sensory stimuli. My

colleagues and I are investigating the

mechanisms by which neurotransmitters

such as glutamate and purines affect

neurones in the dorsal horn. We are

examining the effects of neurotransmitters

on ionic currents and on the level of the

ubiquitous intracellular messenger calcium.

We are also studying the regulation of

glutamate receptors by tyrosine phosphorylation.

Since sensory neurones in the

dorsal horn participate in transmitting pain

information, one of the ultimate goals of

my work is to establish a scientific basis for

future advances in the treatment of pain.

Woolf CJ, Salter MW. Neuronal plasticity –

increasing the gain in pain. Science 2000;288:

1765-1768.

Yu X-M, Salter MW. Src, a molecular switch

governing gain control of synaptic transmission

mediated by N-methyl-D-asparate receptors.

Proc Natl Acad Sci U S A 1999;96:7697-7704.

Appointed to the Department of Physiology and

the Institute of Medical Science at the University

of Toronto. External support provided by Canadian

Institutes of Health Research, Canadian Stroke

Network, National Institutes of Health, and Ontario

Neurotrauma Foundation.

Bibudhendra Sarkar, Structural

Biology & Biochemistry: Proteins

of metal transport and effects of

heavy metals in the environment

In my laboratory, we are elucidating the

specific mechanisms of transportation of

metals across membranes to perform their

essential functions and the accumulation

of toxic amounts of metals that become

a health hazard. The recent discovery of

Wilson and Menkes disease genes allows

us to investigate copper transport on the

molecular level. We carry out structural

studies of the copper-transporting ATPase

of Wilson and Menkes diseases by x-ray

absorption spectroscopy, mass spectrometry,

x-ray crystallography, and nuclear magnetic

resonance. We are also attempting to

develop rational treatments for these two

genetic diseases. We are investigating the

metalloproteomics proteomics of cell

organelles to determine the factors responsible

for the specificity of transport activity,

the effect of heavy metals in the environment,

and their impact on human health.

Sarkar B. Copper transport and its defect in Wilson

disease: characterization of the copper-binding

domain of Wilson disease ATPase. J Inorg Biochem

2000;79:187-191.

DiDonato M, Hsu H-F, Narindrasorasak S,

Que L Jr, Sarkar B. Copper-induced conformational

changes in the N-Terminal domain of Wilson

disease copper-transporting ATPase. Biochemistry

2000;39:1890-1896.

Appointed to the Department of Biochemistry

at the University of Toronto. External support

provided by Canadian Institutes of Health Research.

Russell Schachar, Brain & Behaviour

Research: Attention-deficit

hyperactivity disorder: Cognition,

genes, and the brain

Attention-deficit hyperactivity disorder

(ADHD) is a common and impairing

psychiatric illness in childhood. My

research combines cognitive, behavioural,

genetic, and brain-imaging strategies to

find the causes and improve the treatments

of ADHD. My colleagues and I have

found compelling evidence that ADHD

is associated with specific cognitive deficits,

and we have identified several genetic

factors that play a role in the disorder.

We are speeding up the search for the

causes of ADHD by linking our genetic

research with our studies of cognitive

deficit, acquired brain injury, and the brain

basis of the disorder. We use novel imaging

techniques to measure brain structure and

function when subjects perform tasks

requiring particular cognitive processes and

when they take medications for ADHD.

Mota VL, Schachar R. Reformulating attentiondeficit/hyperactivity

disorder according to signal

detection theory. J Am Acad Child Adolesc Psychiatry

2000;39:1144-1151.

Schachar R, Mota V, Logan G, Tannock R, Klim P.

Confirmation of an inhibitory control deficit in

attention-deficit/hyperactivity disorder. J Abnorm

Child Psychol 2000;28:227-235.

Appointed to the Department of Psychiatry at the

University of Toronto. External support provided by

Canadian Institutes of Health Research, National

Institutes of Health, Ontario Mental Health

Foundation, Psychiatry Endowment Fund, and

Purdue Frederick.

Stephen Scherer, Genetics

& Genomic Biology: Genome

analysis: Application to the study

of human disease

My research group is actively contributing

to the molecular characterization of human

chromosome 7 as part of the international

Human Genome Project. We are deciphering

the genetic information encoded

by DNA to identify novel genes that

contribute to imprinting, cancer progression,

and developmental disorders. The

group has also focused on identifying the

genes that cause epilepsy and autism.

We recently identified a disease gene for

progressive myoclonus epilepsy and are now

studying the function of the gene’s protein

in normal and abnormal development.

Kobayashi K, Sinasac DS, Iijima M, Boright AP,

Begum L, Lee JR, Yasuda T, Ikeda S, Hirano R,

Terazono H, Crackower MA, Kondo I, Tsui L-C,

Scherer SW, Saheki T. The gene mutated in adultonset

type II citrullinaemia encodes a putative

mitochondrial carrier protein. Nat Genet

1999;22:159-163.

Vincent JB, Herbrick J-A, Gurling HMD, Bolton

PF, Roberts W, Scherer SW. Identification of a novel

gene on chromosome 7q31 that is interrupted by a

translocation breakpoint in an autistic individual.

Am J Hum Genet 2000;67:510-514.

Appointed to the Department of Molecular and

Medical Genetics at the University of Toronto.

External support provided by Canada Foundation

for Innovation, Canadian Genetic Diseases Network,

Canadian Institutes of Health Research, Cure

Autism Now, Premier’s Research Excellence Award,

and The Hospital for Sick Children Foundation.

Philip Sherman, Infection,

Immunity, Injury & Repair Research:

Host epithelial-cell responses

to infection with gastrointestinal

bacterial pathogens

My laboratory is characterizing host

epithelial cell-signalling responses after

infection with two emerging gastrointestinal

bacterial pathogens, enterohaemorrhagic

Escherichia coli O157:H7 and

Helicobacter pylori. These studies use

complementary in vitro models of bacterial

adhesion, in vivo animal models of human

disease, and clinical research protocols

for children and adolescents. An improved

understanding of how these bacteria

interact with host-cell surfaces should lead

to the development of novel methods to

prevent and treat human disease.

Jones NL, Islur A, Haq R, Mascarenhas M,

Karmali MA, Perdue MH, Zanke BW, Sherman

PM. Escherichia coli Shiga toxins induce apoptosis

in epithelial cells that is regulated by the Bcl-2

family. Am J Physiol 2000;278:G811-G819.

Day AS, Jones NL, Lynett JT, Jennings HA,

Fallone CA, Beech R, Sherman PM. cagE is

a virulence factor associated with Helicobacter

pylori-induced duodenal ulceration in children.

J Infect Dis 2000;181:1370-1375.

Holder of a Tier I Canada Research Chair.

Appointed to the Departments of Paediatrics,

Laboratory Medicine, and Pathobiology, and the

Institute of Medical Science at the University of

Toronto. External support provided by Canadian

Association of Gastroenterology, Canadian

Institutes of Health Research, Institut Rosell,

Lallemand Inc., and The Hospital for Sick Children

Foundation.

Mary Lou Smith, Brain & Behaviour

Research: Behavioural and

neuropsychological correlates of

central nervous system dysfunction

during development

My research examines the behavioural and

neuropsychological consequences of a

variety of disorders of the central nervous

system in children. My colleagues and

I are longitudinally following children with

epilepsy treated with surgical excision or

medication . We are examining the

cognitive, academic, social, emotional,

and behavioural effects of epilepsy and its

impact on the family. We are also interested

in the long-term effects of surgery on

children and are beginning to study its

outcomes in young adulthood. In another

line of research focused on determining

the nature, frequency, and correlates of

psychological impairment arising from

infection with the human immunodeficiency

virus (HIV), we are monitoring

the developmental, behavioural, and

cognitive status of children born with HIV.

Billingsley RL, Smith ML, McAndrews MP.

Material-specific and non-specific attention deficits

in children and adolescents following temporal-lobe

surgery. Neuropsychologia 2000;38:292-303.

Elliott, IM, Lach L, Smith ML. Adolescent and

maternal perspectives of quality of life and

neuropsychological status following epilepsy surgery.

Epilepsy Behav 2000;1:406-417.

Appointed to the Department of Psychology at the

University of Toronto. External support provided by

Ontario Mental Health Foundation.

Research Institute

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Research activities

Annual Report 2000-2001

78

O. Carter Snead III, Brain &

Behaviour Research: Mechanisms

of epileptogenesis in animal models

of refractory epilepsy

My laboratory’s goal is to develop animal

models of epilepsy syndromes unique to

children and to investigate mechanisms

of epileptogenesis in these models.

Recently, we have developed, characterized,

and standardized a rat and mouse model

of atypical absence epilepsy by inhibiting

cholesterol synthesis in the brain with

AY 9944 (AY) during postnatal brain

development. This model is clinically

relevant because it reliably mirrors

the electroencephalographic, behavioural,

pharmacological, and developmental

characteristics of the human condition.

In contradistinction to typical absence

epilepsy, hippocampal circuitry shows

epileptiform activity during atypical absence

seizure activity in the AY model, suggesting

that whether absence epilepsy is typical or

atypical, it seems to be circuitry-dependent.

We are currently focusing on putative γaminobutyric

acid receptor (GABABR) mediated mechanisms in this new model,

particularly putative perturbations of the

molecular biology of the GABABR. Snead OC III, Banerjee PK, Burnham M,

Hampson D. Modulation of absence seizures by the

GABAA receptor: a critical role for metabotropic

glutamate receptor 4 (mGluR$). J Neurosci

2000;20:6218-6224.

Cortez MA, McKerlie C, Snead OC III. Model of

atypical absence seizures. EEG, pharmacological,

and developmental characterization. Neurology

2001;56:341-349.

Holder of the Bloorview Childrens Hospital Chair

in Paediatric Neuroscience at The Hospital for Sick

Children. Appointed to the Departments of

Paediatrics, Medicine, and Pharmacology at the

University of Toronto. External support provided by

Canada Foundation for Innovation, Bloorview

Childrens Hospital Foundation, Canadian Institutes

for Health Research, National Institutes of Health,

Ontario Research and Development Challenge Fund,

Paediatric Consultants, and The Hospital for Sick

Children Foundation.

Etienne Sochett, Population Health

Sciences: Diabetic nephropathy

I study the determinants of

microalbuminuria expression in puberty

in adolescents with type 1 diabetes.

My colleagues and I are following a cohort

of adolescents from early puberty until the

onset of microalbuminuria to ascertain

causative and predictive factors. All

planned measurements (kidney size,

ambulatory blood pressure, sodium-lithium

countertransport, Haemoglobin A1c, and

urinary albumin excretion rate are

complete. I am also studying renal function

and early ambulatory blood-pressuremonitoring

abnormalities in adolescents

with type 1 diabetes. Eleven of 14 subjects

(7 with normal and 7 with high nightto-day

ratios on ambulatory blood-pressure

monitoring) have been studied to date.

The results suggest that those with high

night-to-day ratios are hyperfiltering and

have activation of the local (kidney) reninangiotensin

system.

Parikh A, Sochett EB, McCrindle BW, Dipchand A,

Daneman A, Daneman D. Carotid artery

distensibility and cardiac function in adolescents with

type 1 diabetes. J Pediatr 2000;137:465-469.

O’Hayon BE, Cummings EA, Daneman D,

Ossip MG, Lawson ML, Sochett EB. Does dietary

protein intake correlate with markers suggestive

of early diabetic nephropathy in children and

adolescents with type 1 diabetes? Diabet Med

2000;17:708-712.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Banting and Best Diabetes Centre, Ministry of

Health and Long-Term Care, and The Hospital for

Sick Children Foundation.

Bonnie Stevens, Population Health

Sciences: Pain assessment and

management in infants and children

The scientific basis underlying pain

in infants and children has expanded

exponentially over the past decade.

My colleagues and I are determining the

optimal approaches for assessing pain

in healthy infants and children, as well

as those with cognitive and neurologic

impairments. We are also determining the

efficacy and safety of interventions to

prevent or alleviate acute pain, the impact

of consistent pain management, and factors

that influence health professionals’

integration of pain research into clinical

practice. Finally, we are examining how

pain influences the quality of life of

children with chronic illness and how

alternate models of health care delivery,

such as home care, affect child, family,

and economic outcomes.

Stevens B, Johnston C, Franck L, Petryshen P,

Jack A, Foster G. The efficacy of developmentally

sensitive interventions and sucrose for relieving

procedural pain in very low birth weight neonates.

Nurs Res 1999;48:35-43.

Stevens B, Gibbins S, Franck L. Treatment of pain

in the neonatal intensive care unit. Pediatr Clin

North Am 2000;47:633-650.

Holder of the Signy Hildur Eaton Chair in

Paediatric Nursing Research at The Hospital for

Sick Children. Appointed to the Faculty of Nursing

and the Department of Paediatrics at the

University of Toronto. External support by Health

Canada, Canadian Institutes of Health Research,

Heart and Stroke Foundation of Ontario, Ministry

of Health and Long-Term Care, Premier’s Research

Excellence Award, and The Hospital for Sick

Children Foundation.

Neil Sweezey, Lung Biology:

Lung development: Glucocorticoid

receptor and novel genes, and

hormonal modulation of ion transport

My research team investigates the

hormonal regulation of the epithelial

sodium channel and the cystic fibrosis

transmembrane conductance regulator.

These ion channels are believed to play

important roles in the absorption of liquid

in the lungs at birth or in pulmonary

oedema, and in the hydration of the layer

of liquid that lines the airway surface.

In collaboration with Dr. Feige Kaplan

(at McGill University), we examine the

glucocorticoid receptor, a key factor that

controls lung maturation during late

gestation, to identify glucocorticoidglucocorticoid

receptor-responsive genes

important to lung development. In another

related study of the function of novel

glucocorticoid-responsive genes cloned

from fetal lung, we have found that the

first of these, LGL1, is important in the

formation of airway branches in early

lung development.

Kaplan F, Ledoux P, Kassamali FQ, Gagnon S,

Post M, Koehler D, Deimling J, Sweezey NB.

A novel developmentally regulated gene in lung

mesenchyme: homology to a tumor-derived trypsin

inhibitor. Am J Physiol 1999;271:L1027-L1036.

Zhang C, Sweezey NB, Gagnon S, Muskat B,

Koehler D, Post M, Kaplan F. A novel karyopherinβ

homolog is developmentally and hormonally

regulated in fetal lung. Am J Respir Cell Mol Biol

2000;22:451-459.

Appointed to the Departments of Paediatrics and

Physiology, and the Institute of Medical Science

at the University of Toronto. External support

provided by Canadian Cystic Fibrosis Foundation

and Canadian Institutes of Health Research.

Anna Taddio, Population

Health Sciences: Prevention

and management of pain in the

newborn infant

Hospitalized newborn infants undergo

many painful procedures without the

benefits of analgesia. In previous studies,

my colleagues and I demonstrated that

untreated newborn circumcision pain has

long-term effects on infant pain behaviours

four to six months after the procedure and

that local anaesthetics can minimize these

long-term effects. Our recent studies focus

on whether infants who experience

repeated painful procedures learn to

anticipate pain because they have learned

the steps involved in painful procedures

and on whether they demonstrate more

pain during the same procedure over time.

We have prepared position statements on

the prevention and management of pain

and stress in the newborn that have been

endorsed by the American Academy of

Pediatrics, Canadian Paediatric Society,

Fetus and Newborn Committee, and the

International Group of Pain Researchers.

American Academy of Pediatrics (Committee on

Fetus and Newborn; Committee on Drugs; Section on

Anesthesiology; and Section on Surgery), Canadian

Paediatric Society (The Fetus and Newborn

Committee), Taddio A, Stevens B. Prevention and

management of stress and pain in the newborn.

Pediatrics 2000;105:454-461, and Paediatr Child

Health 2000;5:31-38.

International Evidence-Based Group for Neonatal

Pain. Consensus statement for the prevention and

management of pain in the newborn infant. Arch

Pediatr Adolesc Med 2001;155:173-180.

Appointed to the Department of Pharmacy at the

University of Toronto. External support provided

by The CSHP Research and Education Foundation.

Chet Tailor, Infection, Immunity,

Injury & Repair Research:

Generation of gene therapy relevant

retrovirus vectors that efficiently

infect specific target cells

Murine leukaemia viruses (MLVs) and

viruses related to MLVs are being used to

deliver genes into human cells. However,

these viruses infect a variety of humancell

types and cannot be used to infect

specific cells in gene-therapy studies.

Although subsequent modification of

the viral-envelope glycoprotein allows the

viruses to bind to cell-surface proteins or

receptors expressed on specific cells, the

infections of the specific cells have been

inefficient. To understand how envelope

modifications affect infection efficiencies,

my laboratory has begun investigations

to determine the mechanism of interaction

of MLV-related viral envelopes with their

specific receptors. These studies also

include identifying and characterizing new

retroviral receptors. Our goal is to generate

retrovirus vectors that efficiently infect

specific target cells.

Tailor CS, Nouri A, Kabat D. A comprehensive

approach to mapping the interacting surfaces of

murine amphotropic and feline subgroup B leukemia

viruses with their cell surface receptors. J Virol

2000;74:237-244.

Tailor CS, Nouri A, Lee CG, Kozak C, Kabat D.

Cloning and characterization of a cell surface receptor

for xenotropic and polytropic murine leukemia

viruses. Proc Natl Acad Sci U S A 1999;96:927-932.

Appointed to the Department of Molecular and

Medical Genetics at The University of Toronto.

Research Institute

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Research activities

Annual Report 2000-2001

80

Rosemary Tannock, Brain &

Behaviour Research: Characterization

and treatment of attention-deficit

hyperactivity disorder and

reading disorder

My clinical research program focuses on

attention-deficit hyperactivity disorder

(ADHD) and reading disorder (RD),

both of which are prevalent neurocognitive

disorders and co-occur more often than

expected by chance. The cause of this

association is unknown, but it complicates

diagnosis and treatment. In collaboration

with my colleagues, I am using multiple

research approaches to investigate

1) working memory, inhibitory-control,

and timing mechanisms because they

may be implicated in both disorders;

2) the neurocognitive expression of these

disorders in childhood and adolescence

to inform us about developmental change;

3) the effects of specific drugs on these

cognitive mechanisms to inform us about

their neural substrate; 4) the effectiveness

of single and combined modality treatment

for children with ADHD+RD (stimulant

medication, specific academic remediation);

and 5) the genetics of these disorders.

Purvis K, Tannock R. Phonological processing, not

inhibitory control, differentiates ADHD and reading

disability. J Am Acad Child Adolesc Psychiatry

2000;39:485-494.

Tannock R, Martinussen R, Frijters J. Naming

speed performance and stimulant effects indicate

effortful, semantic processing deficits in attentiondeficit/hyperactivity

disorder. J Abnorm Child

Psychol 2000;28:237-252.

Appointed to the Department of Psychiatry, the

Institute of Medical Science, and the Ontario

Institute for Studies in Education at the University

of Toronto. External support provided by Canadian

Institutes of Health Research, Eli Lilly Canada Inc.,

Ontario Mental Health Foundation, and Psychiatry

Endowment Fund.

Keith Tanswell, Lung Biology:

Mechanisms of lung injury and repair

Pulmonary oxygen toxicity is one

contributing factor to bronchopulmonary

dysplasia, a chronic fibrotic lung injury

that occurs in very premature infants.

Functional or surgical pneumonectomy

is a consequence of various congenital

lung defects; the primary cause of death

in persons with cystic fibrosis is lung injury.

My colleagues and I have developed in vivo

and in vitro rat and mouse models of

bronchopulmonary dysplasia, cystic fibrosis,

and pneumonectomy to define the cellular

mechanisms that contribute to the injury,

repair, and compensatory growth of the

lung. Experimental gene transfer is a potent

tool for defining the critical roles of putative

mediators. Since gene therapy may become

a clinically applicable approach to intervention,

collaborative efforts with other

members of the Lung Gene Therapy

Program have focused on developing cellspecific

and more effective vehicles for

intrapulmonary gene transfer.

Jankov RP, Luo X, Cabacungan J, Belcastro R,

Frndova H, Lye SJ, Tanswell AK. Endothelin-1 and

O2-mediated pulmonary hypertension in neonatal

rats: a role for products of lipid peroxidation. Pediatr

Res 2000;48:289-298.

Buch S, Han RNN, Cabacungan J, Wang J, Yuan S,

Belcastro R, Deimling J, Jankov R, Luo X, Lye SJ,

Post M, Tanswell AK. Changes in expression of

platelet-derived growth factor and its receptors in the

lungs of newborn rats exposed to air or 60% O2. Pediatr Res 2000;48:423-433.

Holder of the Women’s Auxiliary Chair in

Neonatology at The Hospital for Sick Children.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided

by Canadian Cystic Fibrosis Foundation, Canadian

Institutes of Health Research, and The Hospital for

Sick Children Foundation.

Ingrid Tein, Metabolism Research:

Study of the pathophysiology

of new genetic defects in fatty

acid oxidation

My research group focuses on the clinical,

biochemical, and molecular characterization

of normal and abnormal human fatty acid

oxidation (FAO), including the defects

of the plasmalemmal carnitine (Cn)

transporter, carnitine palmitoyltransferase

(CPT) 1 and 2, and intramitochondrial

β-oxidation. Our research includes the

characterization of two phenotypes of CPT

deficiency, investigation of recurrent

childhood myoglobinuria, identification

of a new muscle phenotype of SCHAD

deficiency, demonstration of impaired Cn

uptake in primary systemic Cn-responsive

cardiomyopathy, study of mechanisms of

secondary Cn deficiency, identification of

a novel phenotype of SCAD deficiency,

development of new therapies for LCHAD

deficiency, and biochemical and molecular

characterization of the human plasmalemmal

Cn transporter. Our goals are

to identify the integral components

and regulators of the Cn transporter,

characterize the tissue-specific distribution

of the defect, and identify further new

mutations in the transporter gene, and

develop new FAO therapies.

Lamhonwah A-M, Tein I. GFP-human highaffinity

carnitine transporter OCTN2 protein:

subcellular localization and functional restoration

of carnitine uptake in mutant cell lines with the

carnitine transporter defect. Biochem Biophys Res

Commun 1999;264:909-914.

Tein I, Haslam RHA, Rhead WJ, Bennett MJ,

Becker LE, Vockley J. Short-chain acyl-CoA

dehydrogenase deficiency. A cause of ophthalmoplegia

and multicore myopathy. Neurology 1999;52:366-372.

Appointed to the Departments of Paediatrics, and

Laboratory Medicine and Pathobiology at the

University of Toronto. External support provided by

Heart and Stroke Foundation of Ontario and Sigma-

Tau Pharmaceuticals, Inc.

Raymond Tellier, Infection,

Immunity, Injury & Repair Research:

Studies of viral genetics

My studies of viral genetics include

1) studies of hepatitis B and hepatitis C

viruses to investigate the role of quasispecies

in infection chronicity, the severity

of disease, and the development of new

methods to characterize the structure of

the mutant swarm in quasispecies to better

develop predictors of disease evolution;

2) genetic studies of Coxsackie B viruses;

and 3) in collaboration with Dr. Martin

Petric’s laboratory, genetic and biological

studies of toroviruses, which are newly

described agents of gastroenteritis.

Other research interests also include

the application of molecular biology

to clinical virology.

Martino TA, Tellier R, Petric M, Irwin DM,

Afshar A, Liu PP. The complete consensus sequence

of coxsackievirus B6 and generation of infectious

clones by long RT-PCR. Virus Res 1999;64:77-86.

Johnson J, Nelson S, Petric M, Tellier R.

Comprehensive PCR-based assay for detection and

species identification of human herpesviruses. J Clin

Microbiol 2000;38:3274-3279.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Canadian

Institutes of Health Research.

Paul Thorner, Structural Biology &

Biochemistry: Structural biology and

biochemistry

Alport syndrome is a progressive hereditary

renal disease linked to structural abnormalities

in the glomerular basement membrane

caused by mutations in the genes encoding

the α3, α4, or α5 chains of type IV collagen.

The most common form is X-linked

and involves the COL4A5 gene. Only

dialysis and kidney transplantation are

available for those patients in end-stage

renal disease. The goal of my project is to

develop gene therapy for X-linked Alport

syndrome that uses the unique canine

model my colleagues and I have characterized.

In doing this work, we will also

be investigating the coordination of the

production of the α3, α4, or α5 chains,

and their roles in glomerular basement

membrane development, structure, and

long-term maintenance.

Zheng K, Harvey S, Sado Y, Naito I, Ninomiya Y,

Jacobs R, Thorner PS. Absence of the α6(IV) chain

of collagen type IV in Alport syndrome is related to

a failure at the protein assembly level and does not

result in diffuse leiomyomatosis. Am J Pathol

1999;154:1883-1892.

Heikkilä P, Tryggvason K, Thorner PS. Animal

models of Alport syndrome: advancing the prospects

for effective human gene therapy. Exp Nephrol

2000;8:1-7.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Canadian

Institutes of Health Research and National

Institutes of Health.

Teresa To, Population Health

Sciences: Health services and

outcomes research

My research centres on the analysis of

administrative and national survey data

to assess different aspects of health care

services and health outcomes. The Ontario

Ministry of Health recently funded my

research team’s paediatric asthma

surveillance proposal for the next 3 years.

In this study, we will develop a method

for ongoing childhood asthma surveillance

and measure the long-term health outcomes

of patients with asthma. Health

Canada also funded our child development

study in which we used Canadian population-based

data to elucidate how biological

risk markers, child characteristics,

the home environment, and socioeconomic

background affect the development of

children aged 2 to 3 years. In addition

to my research, I represent the hospital

as an advisor on the Ontario Ministry of

Health’s Asthma Strategic Plan of Action

Committee for 2000-2001.

To T, Cadarette SM, Liu Y. Biological, social and

environmental correlates of preschool development.

Child Care Health Dev 2001;27:187-200.

To T, Cadarette SM, Liu Y. Child care arrangement

and preschool development. Can J Public Health

2000;91:418-422.

Appointed to the Departments of Public Health

Sciences and Paediatrics, and the Institute for

Medical Science at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Health Canada, and Ministry

of Health and Long-Term Care.

Research Institute

81


Research activities

Annual Report 2000-2001

82

William Trimble, Cell Biology:

Molecular mechanisms of

membrane fusion

All cells contain membranes that

compartmentalize their interior and

protect them from the external environment.

The movement of molecules

throughout the cell (including the secretion

of proteins, hormones, and neurotransmitters)

requires specific regulated

fusion of these membranes. My laboratory

is identifying and studying the proteins

required for membrane fusion, using

molecular, genetic, and cell biological

techniques. Unexpectedly, we have found

that a set of proteins known to be required

for the completion of cell division also

acts to regulate membrane fusion. Current

research is aimed at further characterizing

the relationship between intracellular

membrane traffic and sealing the external

membrane after cell division.

Stewart BA, Mohtashami M, Trimble WS,

Boulianne GL. SNARE proteins contribute to

calcium cooperativity of synaptic transmission.

Proc Natl Acad Sci U S A 2000;97:13955-13960.

Beites C, Xie H, Bowser R, Trimble WS. The septin

CDCrel-1 binds syntaxin and inhibits exocytosis.

Nat Neurosci 1999;2:434-439.

Appointed to the Department of Biochemistry

at the University of Toronto. External support

provided by Canadian Institutes of Health

Research, National Cancer Institute of Canada,

Natural Sciences and Engineering Research Council

of Canada, and The Arthritis Society.

Lap-Chee Tsui, Genetics & Genomic

Biology: Molecular genetics of

cystic fibrosis, human chromosome 7,

and other diseases

My laboratory’s research shows that the

severity of cystic fibrosis (CF) symptoms

is not only determined by mutations in the

CFTR gene. Based on information derived

from our study with a mouse model, we

have mapped the first CF-modifier gene to

human chromosome 19. Detailed analysis

is underway to identify the gene that is

responsible for meconium ileus in neonates

with CF. We have also developed a mouse

model system and identified several

chromosome regions which might contain

genes that influence the severity of lung

disease in patients with CF. In our

chromosome 7 project, we are developing

mouse models to understand the molecular

basis of Williams syndrome, a multisystem

disorder caused by the deletion of a

segment of this chromosome, and the

pathophysiology of the late-onset form

of citrullinaemia.

Zielenski J, Corey M, Rozmahel R, Markiewicz D,

Aznarez I, Casals T, Larriba S, Mercier B, Cutting

GR, Krebsova A, Macek M Jr, Langfelder-Schwind

E, Marshall BC, DeCelie-Germana J, Claustres M,

Palacio A, Bal J, Nowakowska A, Ferec C, Estivill X,

Durie P, Tsui L-C. Detection of a cystic fibrosis

modifier locus for meconium ileus on human

chromosome 19q13. Nat Genet 1999;22:128-129.

Nichol CJ, Zielenski J, Tsui L-C, Wells PG. An

embryoprotective role for glucose-6-phosphate

dehydrogenase in developmental oxidative stress and

chemical teratogenesis. FASEB J 2000;14:111-127.

Holder of the H.E. Sellers Chair in Cystic Fibrosis at

The Hospital for Sick Children. Appointed to the

Department of Molecular and Medical Genetics at

the University of Toronto. External support

provided by Canada Foundation for Innovation,

Canadian Cystic Fibrosis Foundation, Canadian

Genetic Diseases Network, Canadian Institutes of

Health Research, Howard Hughes Medical Institute,

National Institutes of Health, Ontario Innovation

Trust, and The Hospital for Sick Children Foundation.

Wendy Ungar, Population Health

Sciences: Access to pharmaceutical

benefits, methods of economic

evaluation, and use of health services

A barrier to health care, such as full

or partial out-of-pocket payment for

medications, may lead to negative health

outcomes in children with asthma. My

colleagues and I are examining the impact

of pharmaceutical cost-sharing policies on

children in Ontario by comparing health

outcomes, use of health services, and

quality of life for children with asthma who

have full or partial drug plan coverage with

those in children with asthma without

drug-plans. Additional research focuses

on measurement issues pertaining to the

economic assessment of interventions,

services, and programs for children. We are

conducting a literature review and quality

appraisal of published paediatric economic

evaluations to identify methodological gaps

and construct a framework for future health

economic-methods research.

Ungar W, Coyte PC, The Pharmacy Medication

Monitoring Program Advisory Board. Measuring

productivity losses in asthma patients. Health Econ

2000;9:37-46.

Ungar WJ, Coyte PC, Chapman KR, MacKeigan L.

The patient level cost of asthma in adults in south

central Ontario. The Pharmacy Medication

Monitoring Program Advisory Board. Can Respir J

1998;5:463-471.

Appointed to the Department of Health

Administration at the University of Toronto and

the Father Sean O’Sullivan Research Centre, St.

Joseph’s Hospital, McMaster University. External

support provided by Canadian Institutes of Health

Research, Ministry of Health and Long-Term Care,

The Hospital for Sick Children Foundation, and

The Ontario Respiratory Care Society/Ontario

Lung Association.

Jiri Vajsar, Brain & Behaviour

Research: Clinical aspects of

neuromuscular diseases

New advances in the diagnosis and

treatment of neuromuscular diseases

have been the main focus of my research.

In collaboration with colleagues in the

Department of Molecular Biology and

Neuropathology, I have been defining

subgroups of myopathic and neurogenic

disorders. This activity has diagnostic

implications for and relevance to future

therapeutic trials. Apart from the involved

molecular biology and pathology laboratories,

my electromyography laboratory has

developed more sensitive techniques to

study neuromuscular disorders.

Vajsar J, Ackerley C, Chitayat DA, Becker LE. Basal

lamina abnormality in the skeletal muscle of Walker-

Warburg syndrome. Pediatr Neurol 2000;22:139-

143.

Bril V, Allenby K, Midroni G, O’Connor PW, Vajsar

J. IGIV in neurology — evidence and recommendations.

Can J Neurol Sci 1999;26:139-152.

Appointed to the Department of Paediatrics at the

University of Toronto. External support provided by

Muscular Dystrophy Association (USA) and The

Hospital for Sick Children Foundation.

Lu-Yang Wang, Brain & Behaviour

Research: Neuronal communication in

the developing brain

Communication between neurons is

achieved primarily through synapses.

Using a single giant synapse in the mouse

auditory brainstem, my colleagues and I

study the cellular and molecular mechanisms

that regulate 1) the presynaptic release

and replenishment of the neurotransmitter

glutamate, and 2) the postsynaptic composition

of glutamate-receptor subunits,

receptor clustering, and gating behaviour

in the early postnatal stages. We use

biophysical and biochemical assays such as

patch-clamping, fluorescence imaging, and

photolysis to investigate functional

development of synaptic transmission.

An understanding of the key factors that

govern the efficacy of synaptic transmission

may provide important insights into

information-coding process and synaptic

plasticity in the developing brain, and help

establish effective therapeutic strategies

and agents against juvenile neurological

disorders such as ataxia, seizure, and

learning deficits.

Wang L-Y. The dynamic range for gain control of

NMDA receptor-mediated synaptic transmission at a

single synapse. J Neurosci 2000;20(RC115):1-5.

Smith TC, Wang L-Y, Howe JR. Heterogeneous

conductance levels of native AMPA receptors. J

Neurosci 2000;20:2073-2085.

Appointed to the Department of Physiology at the

University of Toronto. External support provided by

Canadian Institutes of Health Research and The

EJLB Foundation.

Yu Tian Wang, Brain & Behaviour

Research: Plasma membrane

targeting of ligand-gated

neurotransmitter receptors in

brain function and dysfunction

Glutamate and γ-aminobutyric acid

receptors are two principal neurotransmitter

receptors that mediate

excitatory and inhibitory synaptic

transmission, respectively, in the brain.

These receptors play a crucial role in both

brain function and dysfunction. My colleagues

and I are interested in understanding

the molecular mechanisms

responsible for the intracellular trafficking

and plasma-membrane targeting of these

receptors, and investigating the manner by

which these mechanisms may be altered in

disease processes. The goal is, ultimately,

to be able to treat central nervous disorders,

such as cerebral ischaemia and epilepsy, by

designing new therapeutics that specifically

target these receptors and their pathways.

Liu F, Wan Q, Pristupa Z, Wang YT, Niznik HB.

Direct protein-protein coupling enables cross-talk

between dopamine D5 and gamma-aminobutyric

acid A receptors. Nature 2000;403:274-280.

HY Man, J Lin, W Ju, G Ahmadian-Bahadorani,

LE Becker, M Sheng, Wang YT. Regulation of

AMPA receptor-mediated synaptic transmission by

clathrin-dependent receptor internalization. Neuron

2000;25:649-662.

Appointed to the Department of Laboratory Medicine

and Pathobiology at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Canadian Stroke Network, Heart

and Stroke Foundation of Canada, Heart and Stroke

Foundation of Ontario, Premier’s Research

Excellence Award, and The EJLB Foundation.

Research Institute

83


Research activities

Annual Report 2000-2001

84

Rosanna Weksberg, Genetics

& Genomic Biology:

Overgrowth syndromes

My research program centres on the

molecular analysis of overgrowth

syndromes such as Beckwith-Wiedemann

syndrome (BWS) and Simpson-Golabi-

Behmel syndrome. Investigation of

chromosome 11p15 in patients with BWS

has defined different single gene mutations

and chromosome rearrangements that can,

in an imprinted region of the genome,

result in overlapping clinical phenotypes.

My colleagues and I have defined a variety

of defects in imprinted genes in patients

with BWS. Specifically, only a small

percentage have mutations in the cyclindependent

kinase inhibitor gene, p57KIP2 ,

or defects in imprinting. However,

complete or partial loss of imprinting

occurs in a new differentially methylated

region of intron 10 of the KvLQT1 gene

in 50 per cent of BWS cases. Interestingly,

an antisense transcript LIT shows

concomitant loss of imprinting in these

cases. Currently, we are exploring the roles

of these various molecular lesions in

overgrowth and tumour predisposition.

Smilinich NJ, Day CD, Fitzpatrick GV,

Caldwell GM, Lossie AC, Cooper PR,

Smallwood AC, Joyce JA, Schofield PN, Reik W,

Nicholls RD, Weksberg R, Driscoll DJ, Maher ER,

Shows TB, Higgins MJ. A maternally methylated

CpG island in KvLQT1 is associated with an

antisense paternal transcript and loss of imprinting

in Beckwith-Wiedemann syndrome. Proc Natl Acad

Sci USA 1999;96:8064-8069.

Squire JA, Li M, Perlikowski S, Fei YL, Bayani J,

Zhang ZM, Weksberg R. Alterations of H19

imprinting and IGF-2 replication timing are

infrequent in Beckwith-Wiedemann syndrome.

Genomics 2000;65:234-242.

Appointed to the Departments of Paediatrics,

Molecular and Medical Genetics, and Medical

Genetics and Microbiology, and the Institute

of Medical Science at the University of Toronto.

External support provided by National Cancer

Institute of Canada.

Lori West, Infection,

Immunity, Injury & Repair

Research: Transplantation during

immunologic immaturity

The focus of my research team is the

induction of transplantation tolerance

during immunologic immaturity. Using

a mouse model of neonatal tolerance

induction, we perform in vitro and in vivo

experiments, including heterotopic heart

transplantation, to assess the consequences

of early immune manipulation. Our clinical

goal is to develop a process to induce

tolerance to cardiac grafts during fetal or

neonatal life, after a diagnosis of lethal

congenital cardiac disease. Inducing this

tolerance prepares the very young patient

for heart transplantation when the immune

system is most susceptible to tolerance

induction. Aspects of this work have been

translated into a novel clinical protocol of

heart transplantation across major blood

group incompatibility in infant recipients,

with a survival rate of 80% and a dramatic

decrease in waiting-list mortality.

West LJ, Pollock-Barziv SM, Dipchand AI, Lee KJ,

Cardella CJ, Benson LN, Rebeyka IM, Coles JG.

ABO-incompatible heart transplantation in infants.

N Engl J Med, 2001;344:793-800.

West LJ, Tao K. Neonatal infusion of allogeneic fetal

liver cells induces non-specific acceptance of cardiac

allografts without diminution of alloreactivity to skin

grafts and in vitro assays. J Heart Lung Transplant.

2001;20:173.

Appointed to the Department of Paediatrics at the

University of Toronto.

Carol Westall, Brain & Behaviour

Research: Visual development

I study the development of normal and

abnormal visual systems. I measure

electrical signals evoked by specific visual

stimuli. I study retinal development,

recording retinal function using an

electroretinogram, electrodes placed on

the surface of the eye to pick up visually

induced signals from the retina (sensory

lining at the back of the eye). Using visual

evoked potentials (electrical signals from

the brain response to changing visual

stimuli) I compare techniques for assessing

visual-pathway misrouting in children with

albinism, and the ability of the brain to

respond to simultaneous right- and left-eye

signals (binocular vision) in children with

normal eyes and in those with eye turns

(strabismus). We found that children with

strabismus had a degree of binocular vision.

Eizenman M, Westall CA, Geer I, Smith K,

Chatterjee S, Panton CM, Kraft SP, Skarf B.

Electrophysiological evidence of cortical fusion in

children with early onset esotropia. Invest

Ophthalmol Vis Sci 1999;40:354-362.

Soong F, Levin AV, Westall CA. Comparison of

techniques for detecting visual evoked potential

asymmetry in albinism. J AAPOS 2000;4:302-310.

Appointed to the Department of Ophthalmology

at the University of Toronto. External support

provided by Canadian Institutes of Health Research

and SmithKline Beecham Pharma.

Gregory Wilson, Cardiovascular

Research: Cardiac protection and

biomaterials development

In my studies of cardiac protection strategies,

I am focusing on preconditioning

that, after a brief period of blood-flow

cessation (ischaemia), protects the heart

against a subsequent, much longer period

of ischaemia. I am trying to determine

the key proteins (end effectors) that

produce this protection, concentrating on

ion channels. I am also working on tissue

engineering that involves implants based

on removing all cells, but retaining key

structural proteins, termed the acellular

matrix, from either human or animal

tissue. Potential uses include bladder

reconstruction, blood-vessel bypass, and

heart-valve replacement in children.

Diaz RJ, Losito VA, Mao GD, Ford MK, Backx PH,

Wilson GJ. Chloride channel inhibition blocks the

protection of ischemic preconditioning and hypoosmotic

stress in rabbit ventricular myocardium.

Circ Res 1999;84:763-775.

Merguerian PA, Reddy PP, Barrieras DJ, Wilson GJ,

Woodhouse K, Bägli D, McLorie GA, Khoury AE.

Acellular bladder matrix allografts in the

regeneration of functional bladders: evaluation of

large-segment (>24 cm2 ) substitution in a porcine

model. Br J Urol Int 2000;85:894-898.

Appointed to the Departments of Laboratory

Medicine and Pathobiology, Surgery, and

Physiology, and the Institute of Medical Science

at the University of Toronto. External support

provided by Acellular Matrix Development Inc.,

Canadian Institutes of Health Research, Heart

and Stroke Foundation of Ontario, Materials and

Manufacturing Ontario, and Ontario Research

and Development Challenge Fund.

James Wright, Population

Health Sciences: Outcomes research

in orthopaedics

My research team continues to research

three areas. First, we investigate why the

probability of patients receiving

orthopaedic surgical procedures varies by

geographic area. In the past year, we have

shown a significant unmet need in the use

of total-joint replacement. This research

is relevant to the delivery of many orthopaedic

procedures to improve the quality

of life. We are currently investigating

possible explanations for this variation.

Second, we are studying improved methods

of evaluating the outcome of surgical

procedures. We are investigating the

use and development of patient-specific

measures that deal with patients’ individual

concerns. Finally, we have three ongoing

randomized clinical trials, evaluating

the surgical treatment of 1) idiopathic

scoliosis, 2) paediatric femoral fractures,

and 3) simple bone cysts.

Hawker GA, Wright JG, Coyte PC, Williams JI,

Harvey B, Glazier R, Badley EM. Differences

between men and women in the rate of use of hip

and knee arthroplasty. N Engl J Med 2000;342:

1016-1022.

Wright JG. Evaluating the outcome of treatment:

shouldn’t we be asking patients if they are better?

J Clin Epidemiol 2000;53:549-553.

Holder of the Robert B. Salter Chair in Paediatric

Surgical Research at The Hospital for Sick Children.

Appointed to the Departments of Surgery and

Public Health Sciences at the University of

Toronto. External support provided by Canadian

Arthritis Network, Canadian Institutes of Health

Research, Johnson & Johnson Medical Products,

Ontario Neurotrauma Foundation, Orthopaedic

Research and Education Foundation, Paediatric

Orthopaedic Society of North America, The Arthritis

Society, and University of Toronto.

Herman Yeger, Cancer & Blood

Research: Pathobiology and therapy

of paediatric embryonal tumours

The paediatric embryonal tumours (Wilms

tumour, neuroblastoma, medulloblastoma)

serve as models of tumorigenesis initiated

during fetal organ development. For Wilms

tumour, we are establishing links between

the pathobiology of this cancer and the

functional involvement of autocrine growth

pathways. Our studies will provide a

molecular basis for understanding Wilms

tumour growth, differentiation, and

progression. For neuroblastoma and

medulloblastoma, we have evidence of the

central involvement of the mevalonate

metabolic pathway in tumour growth and

survival. Further studies indicate that diet

relevant phytochemicals (e.g., flavonoids)

are cytotoxic for neuroblastoma and target

the signal transduction pathways governing

growth and survival. Understanding the

molecular mechanisms that regulate

tumour growth, differentiation, and the

survival or apoptotic equilibrium will

facilitate the design of innovative modalities

of therapy that are effective against

aggressive and chemorefractory cancers.

Dimitroulakos J, Ye LY, Benzaquen M, Moore MJ,

Kamel-Reid S, Freedman MH, Yeger H, Penn LZ.

Differential sensitivity of various pediatric cancers

and squamous cell carcinomas to lovastatin-induced

apoptosis: therapeutic implications. Clin Cancer Res

2001;7:158-167.

Macaulay RJ, Wang W, Dimitroulakos J, Becker LE,

Yeger H. Lovastatin-induced apoptosis of human

medulloblastoma cell lines in vitro. J Neurooncol

1999;42:1-11.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by Canadian

Institutes of Health Research.

Research Institute

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Research activities

Annual Report 2000-2001

86

Rae Yeung, Cancer & Blood

Research: The role of superantigens

in autoimmunity

The cause of Kawasaki disease, the most

common cause of acquired heart disease in

children in Canada, is not known. Evidence

in children shows that infections can cause

massive stimulation of the immune system

that damages the coronary arteries and

results in aneurysms. My colleagues and

I have developed an animal model of

Kawasaki disease using an infectious agent

to promote development of coronary

arteritis in young mice. The disease seen in

the young mice parallels that seen in young

children. We have discovered a new

bacterial superantigen that is responsible

for causing heart disease in young mice.

My laboratory is involved in dissecting

the immune response to this new

superantigen and the steps leading to

the damage in the coronary arteries. We

are trying to better understand the role the

immune system plays in Kawasaki disease

and develop novel therapies to better care

for affected children.

Bachmaier K, Neu N, Yeung RSM, Mak T W, Liu P,

Penninger JM. Generation of humanized mice

susceptible to peptide-induced inflammatory heart

disease. Circulation 1999;99:1885-1891.

Honkanen V, Silverman ED, Kumar A, Myones BL,

Taylor G, Yeung RSM. TNFa production by T cells

and macrophages in response to Lactobacillus casei cell

wall extract (LCWE). Pediatr Res 2000;47:561.

Appointed to the Department of Paediatrics

and the Institute of Medical Science at the

University of Toronto. External support provided

by Heart and Stroke Foundation of Ontario and

The Arthritis Society.

Shi-Joon Yoo, Cardiovascular

Research: Evaluation of the

pulmonary veins with magnetic

resonance imaging

Magnetic resonance imaging is increasingly

used for the evaluation of cardiovascular

diseases. My colleagues and I found that

contrast-enhanced magnetic resonance

angiography is the most accurate method

of evaluating the anatomical abnormalities

of pulmonary veins. The significance of

any anatomical narrowing found may be

revealed in an evaluation of the blood-flow

pattern and velocity proximal and distal to

the narrowing with echocardiography or

the velocity-mapping technique of

magnetic resonance imaging. The velocitymapping

technique, however, has not

previously been used to evaluate pulmonary

venous abnormalities. The second stage

of our research on pulmonary veins will

test the utility of the velocity-mapping

technique for the evaluation of

the narrowing of the pulmonary veins.

Yoo S-J, Lee Y-H, Kim ES, Rya HM, Kim MY,

Yang JH, Chun YK, Hong SR. Tetralogy of Fallot

in the fetus: findings at targeted sonography.

Ultrasound Obstet Gynecol 1999;14:29-37.

MacDonald C, Mikhailian H, Yoo S-J,

Freedom RM, Adatia I. Angiographic findings of

persistent primitive hepatic venous plexus with

underdevelopment of the infrahepatic inferior vena

cava in pediatric patients. Am J Roentgenol

2000;175:1397-1401.

Appointed to the Department of Medical Imaging

at the University of Toronto.

Nancy Young, Population Health

Sciences: Assessing the health

of children in the community

I am a core member of the Paediatric

Outcomes Research Team. Using a

combination of quantitative and qualitative

research methods, I develop, assess, and

promote new methods of measuring a

variety of paediatric health care outcomes,

such as physical function, health status,

and quality of life. My major projects

include the assessment of new methods of

delivering health care to children in the

community (e.g., the Tele-HomeCare

project) and the examination of data from

the National Longitudinal Survey of

Children and Youth (NLSCY) to estimate

the health of Canadian children and

explore determinants of health status.

The NLSCY is a survey of Canadian

children completed by Statistics Canada

that contains data on the nature and extent

of health limitations in children.

Young NL, Williams JI, Yoshida KK, Wright JG.

Measurement properties of the Activities Scale for

Kids (ASK). J Clin Epidemiol 2000;53:125-137.

Jacobs B, Young NL, Dick PT, Ipp MM,

Dutkowski R, Davies HD, Langley JM,

Greenberg S, Stephens D, Wang EE. The Canadian

Respiratory Illness and Flu Scale (CARIFS):

development of a valid measure for childhood

respiratory infections. J Clin Epidemiol 2000;53:

793-799.

Appointed to the Departments of Paediatrics,

Health Policy, Management and Evaluation, and

Rehabilitation Science, and the Institute for

Clinical Evaluative Sciences at the University

of Toronto. External support provided by Bloorview

Childrens Hospital Foundation, Health Canada,

Institute for Clinical Evaluative Sciences, and

National Institutes of Health.

Maria Zielenska, Cancer & Blood

Research: Molecular genetic analysis

of paediatric solid tumours

My laboratory’s focus is on the molecular

pathology of the solid tumours of

childhood. A major focus is the use of

molecular biology techniques to identify

and study the genes and biological

pathways of diagnostic or prognostic

importance for children, specifically

sarcomas, neuroblastomas, and brain

tumours. One of our current projects is

to characterize the genetic determinants

of malignancy in rhabdomyosarcoma

with differential-display polymerase chain

reaction and representative difference

analysis. We are also focusing on the

analysis of gene deletion and amplification,

using comparative genomic hybridization.

Additionally, we are doing a comprehensive

cytogenetic and molecular analysis of

paediatric tumours, and correlating the

findings with histological clinical variables

to understand the mechanisms of tumorigenesis

in these tumours. In a further area

of research, we are developing chip-based

technology to aid in the diagnosis of solid

tumours of childhood and the assessment

of their prognosis.

Chan AS, Squires JA, Thorner P, Zielenska M.

Molecular genetic changes in alveolar soft part

sarcoma. Pediatr Pathol Mol Med 2000;18:529-543.

McKenna GJ, Chung SW, Gerrie B, Smith RM,

Chen Y, Squires JA, Zielenska M. A rapid restriction

fragment length polymorphism polymerase chain

reaction-based diagnostic method for identification

of T-cell lymphoproliferative disorders. J Surg Res

1999;85:311-316.

Appointed to the Department of Laboratory

Medicine and Pathobiology at the University of

Toronto. External support provided by National

Cancer Institute of Canada.

Stanley Zlotkin, Metabolism

Research: Novel approaches to food

fortification to prevent micronutrient

deficiencies in infants

The current focus of my research group is

on the mineral metabolism and deficiencies

of infants, particularly of those at risk

of iron and zinc deficiencies. This focus is

in keeping with the large micronutrient

initiative of the United Nations, as

advanced through UNICEF and countryspecific

federal international research

agencies such as the International

Development Research Centre in Canada

and the United States Agency for

International Development in the USA.

We have demonstrated that it is possible

to treat micronutrient deficiencies by using

a novel food-fortification approach.

Our international collaborators are from

the London School of Hygiene and

Tropical Medicine, the University of Accra

in Ghana, the Government of West

Bengal, and nongovernmental agencies

from Canada and the developing world.

Yeung GS, Zlotkin SH. Efficacy of meat and ironfortified

commercial cereal to prevent iron depletion

in cow milk-fed infants 6 to 12 months of age:

a randomized controlled trial. Can J Public Health

2000;91:263-267.

Anderson GH, Zlotkin SH. Developing and

implementing food-based dietary guidance for fat

in the diet of children. Am J Clin Nutr

2000;72(Suppl):1404S-1409S.

Appointed to the Departments of Paediatrics and

Nutritional Sciences at the University of Toronto.

External support provided by Canadian Institutes

of Health Research, Canadian Foundation for

Dietetic Research, Centers for Disease Control and

Prevention, ILSI Research Foundation, The Hospital

for Sick Children Foundation, The International

Development Research Centre, The PATH Foundation

of Canada, and World Vision Canada.

Research Institute

87


Intellectual Property and Commercial Development Office

Dr. Stuart Howe

Intellectual Property and

Commercial Development Office

2000Ð2001 report

The Intellectual Property and Commercial Development Office

(IPCDO) was established to provide integrated services to The

Hospital for Sick Children (HSC) in all areas involving intellectual

property and the commercialization of research activities. The

mission of the IPCDO is to generate contract-based revenues to

support HSC research activities, to derive maximum value from

HSC intellectual property assets and to support HSC researchers

in attaining their scientific goals. The IPCDO continues to strive

towards achieving best practices in academic technology

transfer/management.

In July 2000, Dr. Robert Foldes, director of the IPCDO, left

to assume the role of president and CEO of a Kingston, Ontariobased

start-up company. Dr. Stuart Howe, former Intellectual

Property manager at HSC, was appointed the new director of

the IPCDO in October. Over the past 12 months, the IPCDO

has assumed an increased role in managing various government

research infrastructure award programs, such as Ontario Research

and Development Challenge Fund, Ontario Innovation Trust

and Canada Foundation for Innovation.

In 20002001, the IPCDO managed 136 research contracts

that generated revenues of $12.1 million to support research

(a 24 per cent increase over 1999–2000). Of these contracts,

60 per cent were from industrial sources, with the remainder from

federal or provincial government sources, Centres of Excellence,

non-profit foundations, or subcontracts from academic institutions.

About 60 per cent of these contracts involved clinical research.

The IPCDO also negotiated 124 Material Transfer Agreements,

36 Confidentiality/Non-Disclosure Agreements and two

Collaborative Research and Development Agreements.

In 2000, the Intellectual Property Review Committee (Dr. Hans-

Michael Dosch as the chair, plus standing IPCDO members and

ad hoc scientific reviewers from the HSC community) considered

32 invention disclosures and filed 12 patent applications derived

from the research activities of the following principal investigators/

inventors: C. Roifman; C-c. Hui; P.L. Howell; H.-M. Dosch; C.

Pace-Asciak; G. Koren; J. McGlade; and S. Baruchel.

In 2000, 15 patents were issued to the HSC Research and Development Limited Partnership as follows:

❙ US 5,994,617 “Engraftment of immune-deficient mice with human cells” ( J. Dick et al.)

❙ US 6,017,755 “MADR2 tumor supressor gene” ( J. Wrana)

❙ US 6,020,126 “Rapid Genetic Screening Method” (L.C. Tsui et al.)

❙ US 6,054,134 “Haemophilus Adhesin Protein” (C. Lingwood et al.)

❙ US 6,063,913 “Stable Propagation of Modified CFTR protein cDNA in hetrologous systems” (L.C. Tsui,

J. Rommens et al.)

❙ US 6,063,567 “Method, reagent and kit for diagnosis & targeted screening for retinoblastoma” (B. Gallie et al.)

❙ US 6,103,883 “Glycolipid mimics and methods of use thereof ” (C. Lingwood et al.)

❙ US 6,022,687 “Diagnosis and therapy for Hereditary Haemorrhagic Telangiectasia” (M. Letarte et al.)

❙ US 6,117,675 “Pharmaceuticals containing retinal stem cells” (R. McInnes et al.)

❙ US 6,124,104 “Chromosome 13-linked breast cancer susceptibility gene” ( J. Rommens et al.)

❙ CA 1,341,094 “Diagnosis for Malignant Hyperthermia” (R. Worton et al.)

❙ EP 0746337 “Verotoxin pharmaceutical compositions” (C. Lingwood et al.)

❙ EP 0785727 “Antifreeze polypeptide-expressing microorganisms useful in fermentation and frozen storage of food”

(C. Hew et al.)

❙ AU 711640 “Antifreeze polypeptide-expressing microorganisms useful in fermentation and frozen storage of food”

(C. Hew et al.)

❙ NZ 331165 “Verotoxin pharmaceutical compositions” (C. Lingwood et al.)

The IPCDO negotiated and

executed a total of 28 intellectual

property licenses and option agreements

in the 2000 calendar year

(a 15 per cent increase over 1999)

with the following representative

companies: Pfizer, Inc.; Amersham

Pharmacia Biotech, Inc.;

Taisho Pharmaceutical Co. Ltd.;

Glycodesign, Inc.; Transgenomics,

Inc.; Innogenetics, Inc.;

F. Hoffmann La Roche Ltd.;

Metabolex, Inc.; Janssen Pharmaceuticals,

Inc.; Neurotrophic

Bioscince Inc.; Transition

Therapeutics, Inc.; PE Biosystems;

RIKEN Institute; Curis, Inc.; Kissei

Pharmaceutical Co. Ltd.; Autogen,

Inc.; Genencor, Inc.; and Genzyme

Corporation.

2000 also saw the successful launch

of three companies: Solutions-by-

Sequence, Inc. (B. Gallie);

Diabecore Medical, Inc. (B.

Lougheed, K. Perlman); and

LymphoSign, Inc. (C. Roifman).

The core technology of these

companies was developed at, and

is currently licensed from, The

Hospital for Sick Children.

The growing intellectual property

portfolio managed by the HSC

Research and Development Limited

Partnership achieved annual gross

licensing revenues of $934,000 in

the 2000 calendar year (a 16 per

cent increase over 1999).

During the past year, the IPCDO

successfully in-licensed the rights to

two bioinformatics software packages

from Washington University

and executed the first subscription

agreement for a Canadian research

institution with PE Corporation’s

Celera Genomics Group.

Looking forward to 2001–2002, the

IPCDO will continue to enhance its

infrastructure and service to the

HSC research community and will

focus on securing private-sector

partnerships to enhance the HSC

research environment, and to

develop health-care solutions to

meet the needs of HSC patients.

Research Institute

89


Research Ethics Board

Dr. Max Perlman

An evolving climate for research

involving human subjects

by Dr. Max Perlman

Chair, HSC Research Ethics Board (REB)

The environment in which research in human

subjects is being conducted is changing rapidly.

Over the last couple of years the disclosure

of several “scandals” in the United States

resulted in the temporary cessation of research,

discontinuation of funding of government-

sponsored research in a number of institutions,

and many instances of class action litigation.

Alleged culprits included

individual researchers, ethicists,

members of institutional

review boards (IRBs, termed

research ethics boards or REBs

in Canada), and hospital and

university administrators. Issues

included failures to comply with

a variety of regulations, failure

to adhere to research protocols

post-approval, undeclared

conflicts of interest at all levels,

and the approval of unethical

research.

Of particular significance for

research involving children was

the death of a young participant

in a gene therapy study in the

US, and the approval of alleged

unethical research with children

at a number of the most prestigious

American institutions

providing health care and higher

education. The reaction to these

events included replacement of

the Office for the Protection

of Research Risks (OPRR),

which reported to the National

Institutes of Health (NIH), with

the Office for Human Research

Protection (OHRP), including

a newly appointed physiciandirector

who reports directly

to the Secretary of Health and

Human Services, as well as the

establishment of committees

to formulate new, and upgrade

existing, policies and procedures.

A major new educational

initiative of the NIH is the requirement

that researchers,

administrators, and research

ethics committee members be

certified by their own institutions

to conduct research in human

subjects. Many institutions in the

US have extended this demand

beyond NIH-sponsored research

to include all research.

The HSC Research Ethics

Office and REB have been

involved in a variety of activities

to keep abreast of new developments

in research subject

protection, to comply with new

demands of regulatory agencies,

and to facilitate the work of

researchers. These include:

❙ Over 30 interactive educational

meetings yearly between HSC

researchers and the REB Chair.

❙ A research ethics educational

program to certify researchers

and research staff involved in

research funded by the NIH,

based on the Canadian

TriCouncil Policy Statement

and HSC policies and procedures.

The program consists

of a two-hour lecture, syllabus

and a take-home exam. This

past year, over 100 people took

part in the sessions. Eventually,

all HSC clinical researchers

will be required to obtain

training and certification.

❙ Completion of the recommendations

from the Naimark

Report that relate to the REB.

❙ Definition and delineation

of the roles and responsibilities

of Department and Division

Heads and the Medical

Advisory Committee (MAC)

with regards to clinical

research. The REB reports

to the MAC as well as to the

Chief of Research.

❙ Creation of a REB application

form specific to human tissue

research as well as the enhancement

of existing REB forms,

including greater accessibility.

❙ Development of a Clinical

Research Secretariat, the purpose

of which is to monitor

and ensure compliance of

researchers with HSC policies

and procedures.

❙ Participation in a steering committee

to establish a national

organization of REBS –

the Canadian Association

of Research Ethics Boards

(CAREB). CAREB would provide

a forum for networking,

establishing best practices, and

participating in policy development

at the national level.

Research Institute

91


Research programs

Annual Report 2000-2001

92

Research at The Hospital for

Sick Children is organized into

12 programs – six disciplinary

and six interdisciplinary –

which range the full spectrum of

health research. The disciplinary

research programs are: Genetics

& Genomic Biology, Structural

Biology & Biochemistry, Cell

Biology, Developmental Biology,

Integrative Biology, and

Population Health Sciences.

They focus on areas of funda-

mental biological research,

and reflect increasing levels

of complexity. The interdiscipli-

nary programs are: Brain &

Behaviour Research, Cancer &

Blood Research, Cardiovascular

Research, Infection, Immunity,

Injury & Repair Research, Lung

Biology Research, and

Metabolism Research. The

interdisciplinary programs focus

on clinically relevant problems,

such as a specific disease that

can affect more than one organ

system, or certain organ systems

with specific diseases.

Brain & Behaviour

Research

Research in this program

focuses on the study of the

nervous system, from the

functioning of the brain to

behavioural manifestations.

Head & Senior Scientist

Dr. O. Carter Snead III

Senior Scientists

Dr. Joseph Beitchman

Dr. Maureen Dennis

Dr. Robert Harrison

Dr. Maureen Lovett

Dr. Joanne Rovet

Dr. James Rutka

Dr. Michael Salter

Dr. Russell Schachar

Dr. Rosemary Tannock

Dr. Yu Tian Wang

Scientists

Dr. Cathy Barr

Dr. Zhengping Jia

Dr. Lu-Yang Wang

Senior Associate Scientists

Dr. Laurence Becker

Dr. Eric Bouffet

Dr. William Logan

Associate Scientists

Dr. Marcia Barnes

Dr. Susan Bryson

Dr. James Drake

Dr. Ross Hetherington

Dr. William Logan

Dr. Katherina Manassis

Dr. Blake Papsin

Dr. Mary Lou Smith

Dr. Jiri Vajsar

Dr. Carol Westall

Project Directors

Dr. Michael Balthazor

Dr. Brenda Banwell

Dr. Susan Blaser

Dr. Sylvester Chuang

Irene Elliott

Dr. Tom Humphries

Dr. Abel Ichowicz

Dr. Elizabeth Kerr

Dr. Stephen Kraft

Lucy Lach

Dr. Daune MacGregor

Dr. Molly Malone

Dr. Hiroshi Otsubo

Dr. Elizabeth Pang

Dr. Wendy Roberts

Dr. Jay Rosenfield

Dr. Martin Steinbach

Dr. Jose Luis Perez Velasquez

Dr. Rod Wachsmuth

Dr. Shelly Weiss

Adjunct Scientists

Dr. Terri Lewis

Dr. William McIlroy

Dr. Margot Taylor

Dr. Judith Wiener

Cancer & Blood

Research

Research in this program

focuses on the study of cancer

and blood diseases, deriving

new therapies from basic biol-

ogy to test in clinical trials

and, where appropriate, imple-

ment in clinical practice.

Head

Vacant

Senior Scientists

Dr. Helen Chan

Dr. John Dick

Dr. Michelle Letarte

Dr. Nancy Olivieri

Dr. Herman Yeger

Scientists

Dr. Katryn Furuya

Dr. Ab Guha

Dr. David Malkin

Dr. Rae Yeung

Associate Scientists

Dr. Mohamed Abdelhaleem

Dr. Maria Zielenska

Adjunct Scientist

Dr. Brenda Gallie

Cardiovascular

Research

Research in this program

focuses on the study of the

heart and circulation under

both normal and disease states.

Head & Senior Scientist

Dr. Marlene Rabinovitch

Senior Scientists

Dr. John Coles

Dr. Aleksander Hinek

Dr. Frederick Keeley

Dr. Gregory Wilson

Scientists

Dr. Benoit Bruneau

Dr. Earl Silverman

Associate Scientists

Dr. Robert Hamilton

Dr. Brian McCrindle

Dr. Shi-Joon Yoo

Scientist-Track

Investigators

Dr. Gil Gross

Dr. Lisa Hornberger

Project Directors

Dr. Joel Kirsh

Dr. Kyong Jin Lee

Dr. Jeffrey Smallhorn

Dr. Glen Van Arsdell

Adjunct Scientist

Dr. Graham Wright

Cell Biology

Research in this program

focuses on the study of interac-

tions and processes within and

between cells. This includes

analyses of components such as

organelles, membranes, the

cytoskeleton, the nucleus and

the cell surface/extracellular

matrix, as well as cellular

processes such as signalling and

macromolecular targeting.

Head & Senior Scientist

Dr. Sergio Grinstein

Senior Scientists

Dr. Amira Klip

Dr. Jane McGlade

Dr. Daniela Rotin

Dr. William Trimble

Scientists

Dr. Gregory Hannigan

Dr. Gergely Lukacs

Emeritus Scientist

Dr. Aser Rothstein

Research Institute

93


Research programs

Annual Report 2000-2001

94

Developmental

Biology

Research in this program

focuses on the study of develop-

mental programs in many

organisms. The goal is to under-

stand the processes that control

events leading to the formation

of adult humans from a fertil-

ized egg. This work includes

analyses of gene expression

and regulation, cell and tissue

interactions and signals, and

morphogenesis.

Head & Senior Scientist

Dr. Howard Lipshitz

Senior Scientists

Dr. Gabrielle Boulianne

Dr. Jayne Danska

Dr. Sean Egan

Dr. James Ellis

Dr. Cynthia Guidos

Dr. Chi-chung Hui

Dr. Roderick McInnes

Scientists

Dr. Benjamin Alman

Dr. Julie Brill

Dr. Patricia Harper

Dr. Norman Rosenblum

Associate Scientist

Dr. Christopher Forrest

Scientist-Track

Investigators

Dr. Peter Dirks

Dr. Hans Hitzler

Consultant

Dr. Jon Timothy Westwood

Genetics &

Genomic Biology

Research in this program

focuses on the use of genetic

methods and genomic informa-

tion and technologies to

understand human biology and

mechanisms, both in health

and disease states. This disci-

pline includes studies of gene

organization, genome diversity,

mutation, recombination,

replication, repair, pharmaco-

genetics, and regulation of

gene activities.

Head & Senior Scientist

Dr. Lap-Chee Tsui

Senior Scientists

Dr. Manuel Buchwald

Dr. William Cole

Dr. Jamie Cuticchia

Dr. Denis Grant

Dr. Susanna Lewis

Dr. Stephen Meyn

Dr. Johanna Rommens

Dr. Stephen Scherer

Scientist

Dr. Christopher Pearson

Senior Associate Scientists

Dr. Peter Ray

Dr. Rosanna Weksberg

Associate Scientist

Dr. Elise Héon

Scientist-Track

Investigator

Dr. Berge Minassian

Project Directors

Dr. Raymond Buncic

Shelley Kennedy

Cheryl Shuman

Dr. Ahmad Teebi

Dr. Ikuko Teshima

Adjunct Scientist

Dr. Douglas Biggar

Consultant

Dr. Richard Rozmahel

Infection,Immunity,

Injury & Repair

Research

Research in this program

focuses on the study of invasion

of the body by pathogens and

the body’s defence systems, as

well as mechanisms by which

the body responds to and

repairs internal and external

insults, including autoimmunity

and transplantation.

Head & Senior Scientist

Dr. Chaim Roifman

Senior Scientists

Dr. Amos Cohen

Dr. Hans-Michael Dosch

Dr. Clifford Lingwood

Dr. Philip Sherman

Scientists

Dr. Lori Burrows

Dr. John Chamberlain

Dr. Chet Tailor

Dr. Lori West

Senior Associate Scientists

Dr. Mel Freedman

Dr. Stan Read

Associate Scientists

Dr. Darius Bägli

Dr. Anne Griffiths

Dr. Antoine Khoury

Dr. Martin Petric

Dr. Susan Richardson

Dr. Raymond Tellier

Scientist-Track

Investigators

Dr. Nicola Jones

Dr. Peter Kim

Dr. Anne Opavsky

Project Director

Dr. Lee Ford-Jones

Emeritus Scientist

Dr. Robert Salter

Integrative

Biology

Research in this program

focuses on the study of com-

plex, integrated systems.

This includes analyses of the

immune, endocrine, nervous,

and cognitive systems.

Head & Senior Scientist

Dr. Martin Post (acting)

Senior Scientists

Dr. Peter Durie

Dr. Susan Goldberg

Dr. Mark Henkelman

Dr. Cecil Pace-Asciak

Dr. Cho Pang

Dr. Paul Pencharz

Scientists

Dr. Shinya Ito

Dr. Michael Noseworthy

Dr. Margaret Rand

Senior Associate Scientists

Dr. Geraldine Kent

Dr. Deborah O’Connor

Associate Scientists

Dr. Peter Cox

Dr. Mark Crawford

Scientist-Track

Investigators

Dr. Anthony Chan

Dr. Christopher Macgowan

Project Directors

Daina Kalnins

Dr. Peter Neligan

Adjunct Scientist

Dr. Flavio Coceani

Consultants

Dr. Stephen Cunnane

Dr. Michael Thompson

Lung Biology

Research in this program

focuses on the study of the

normal development of

the lung and the consequences

for the health of children when

normal lung development fails

to occur.

Head & Senior Scientist

Dr. Martin Post

Senior Scientists

Dr. Allan Coates

Dr. Hugh O’Brodovich

Dr. Keith Tanswell

Scientists

Dr. Jim Hu

Dr. Neil Sweezey

Senior Associate Scientist

Dr. Ernest Cutz

Scientist-Track

Investigators

Dr. Brian Kavanagh

Dr. Hiranjan Selvadurai

Project Director

Dr. Ian MacLusky

Emeritus Scientist

Dr. Charles Bryan

Adjunct Scientist

Dr. Greg Downey

Research Institute

95


Research programs

Annual Report 2000-2001

96

Metabolism Research

Research in this program

focuses on the study of how

food is changed into somatic

components and energy, how

the body regulations communi-

cation between organs, and

how the body metabolizes drugs

and toxins.

Head & Senior Scientist

Dr. Brian Robinson

Senior Scientists

Dr. Eve Roberts

Dr. Stanley Zlotkin

Scientist

Dr. Ingrid Tein

Emeritus Scientist

Dr. Gordon Forstner

Population Health

Sciences

Research in this program

focuses on the systematic study

of characteristics of health and

disease and outcomes of treat-

ment modalities in children.

This involves the use of evalua-

tive sciences such as clinical

epidemiology, health economics,

and biostatistics.

Head & Senior Scientist

Dr. James Wright

Senior Scientists

Dr. Maureen Andrew

Dr. Mary Corey

Dr. Gideon Koren

Dr. Colin Macarthur

Dr. Bonnie Stevens

Scientists

Dr. Gabrielle deVeber

Dr. Paul Dick

Dr. Brian Feldman

Dr. Teresa To

Dr. Wendy Ungar

Senior Associate Scientists

Dr. Sylvain Baruchel

Dr. Victor Blanchette

Dr. Desmond Bohn

Dr. Joe Clarke

Dr. Denis Daneman

Dr. David Kenny

Dr. Max Perlman

Associate Scientists

Dr. Upton Allen

Dr. Beverley Antle

Dr. Maru Barrera

Dr. Diane Benoit

Dr. Nancy Benson

Dr. Katherine Boydell

Dr. Debra Katzman

Dr. Susan King

Dr. Anne Matlow

Dr. Gail McVey

Dr. David Nicholas

Dr. Patricia Parkin

Dr. Suzanne Schuh

Dr. Sam Shemie

Dr. Etienne Sochett

Dr. Anna Taddio

Scientist-Track

Investigators

Dr. Manuel Carcao

Dr. Andrew Howard

Dr. Lorelei Lingard

Dr. Patricia Massicotte

Lesley Michell

Dr. Nancy Young

Project Directors

Dr. Gerald Arbus

Dr. Paul Babyn

Marilyn Ballantyne

Wendy Barden

Laura Beaune

Heather Beveridge

Dr. Susan Bradley

Suzanne Breton

Dr. David Chitayat

Dr. Howard Clarke

Christine Curtis

Rita Damignani

Susan Devine

Dr. John Doyle

Lee Dupuis

Adrienne Einarson

Dr. Bruce Ferguson

Simone Fischback

Dr. Jeremy Friedman

Michael Gallo

Dr. Denis Geary

Dr. Chantal Graveline

Dr. Jill Hamilton

Dr. William Hanley

Dr. Jonathan Hellmann

Dr. Robert Hilliard

Dr. Moshe Ipp

Dr. Bernice Krafchik

Dr. Jacob Langer

Dr. Wendy Lau

Dr. Alex Levin

Carol McNair

Ted McNeill

Dr. Aideen Moore

Myla Moretti

Dr. Dennis Scolnik

Dr. Brenda Spiegler

Dr. Sunita Vohra

Shawna Wade

Dr. Diane Wherrett

Kristi Whitney-Mahoney

Dr. Jean-Victor Paul Wittenberg

Dr. Arlene Young

Dr. Ronald Zuker

Adjunct Scientists

Dr. Elizabeth Badley

Dr. Kathryn Ann Boschen

Dr. Judith Globerman

Dr. Ilze Kalnins

Dr. Ralph Manktelkow

Dr. Else Marziali

Dr. Nancy McKee

Dr. Blake Poland

Dr. Denise Reid

Dr. Elaine Wang

Consultants

Mary McAllister

Dr. Patricia McKeever

Emeritus Scientist

Dr. Ingeborg Radde

Structural Biology

& Biochemistry

Research in this program

focuses on the study of the

relationship between molecular

structure and biological func-

tion of proteins and other

macromolecules. The goal is to

gain a better understanding of

the molecular bases of disease

processes.

Head & Senior Scientist

Dr. Bibudhendra Sarkar

Senior Scientists

Dr. Christine Bear

Dr. Joan Boggs

Dr. Charles Deber

Dr. Julie Forman-Kay

Dr. Janet Forstner

Dr. Choy-Leong Hew

Dr. Lynne Howell

Dr. Don Mahuran

Scientist

Dr. Régis Pomès

Senior Associate Scientists

Dr. John Callahan

Dr. Paul Thorner

Associate Scientist

Dr. Khosrow Adeli

Senior Scientists Emeritus

Dr. Mario Moscarello

Dr. Harry Schachter

Research Institute

97


Annual Report 2000-2001 Research funding

98

Research institute expenses

2000-2001 total expenditures (from internal and external

funding) for the year ended March 31, 2001.

Dollar amounts in thousands of dollars (Õ000s)

Internal External Total

$15,240 $30,346 salaries $45,586

1,972 2,382 benefits 4,354

185 10,289 supplies 10,474

256 7,833 capital equipment 8,089

2,344 599 building, renovations

and furniture 2,943

7,172 7,253 other 14,425

$27,169 $58,702 total $85,871

17%

Other

53%

Salaries

12%

Supplies

9%

Equipment

Total internal funding

Internal funding comes largely from community donors, through

The Hospital for Sick Children Foundation, as well as from estates

willed to HSC. This funding is integral to operations of the Research

Institute, as it supports the Research Institute’s infrastructure budget,

which includes scientists’ salaries, support staff, physical plant expenses

and supplies. Philanthropy, in combination with funding from granting

agencies, government and industry, enables the Research Institute to

continue to make advancements in health research.

Dollar amounts in thousands of dollars (Õ000s)

HSC Foundation 21,700

HSC Endowments 1,323

HSC 1,000

J.R. Robertson Estate 865

J.P. Bickell Foundation 1,995

Other 286

Total $27,169

4% Building, renovations

and furniture

5% Benefits

Total external funding

2000-2001 grants from external sources.

number type amount

34 scientist 2,764,636

13 scholarship 734,790

53 research fellowship 1,877,873

207 studentship 2,491,568*

14 summer studentship 36,697

321 total awards $7,905,564

424 research project 34,780,140

40 contract 3,882,356

77 donation 4,077,402

3 conference 31,623

5 equipment 3,384,466

5 maintenance 314,346

25 miscellaneous 4,049,008

4 travel 22,027

37 clinical trial 1,603,219

620 total $52,144,587

941 total $60,050,151

* Includes income from The Hospital for Sick Children

Foundation Graduate Student Awards endowment held

at the University of Toronto.

Sources of external funding

29%

Canadian Institutes

of Health Research

5%

Companies

17%

Other granting

agencies

3%

University

of Toronto

4%

Canadian Cystic

Fibrosis Foundation

4%

Heart and Stroke

Foundation of Ontario

5% Canada Foundation

for Innovation

8% Ontario Research

and Development Challenge Fund

7% The Hospital for Sick Children Foundation

6% National Institutes of Health

6% National Cancer

Institute of Canada

6% Ontario Innovation Trust

Research Institute

99


Annual Report 2000-2001 2000Ð2001 awards to investigators

100

Senior Investigators (Senior and Distinguished Scientists)

program grantor term

Sergio Grinstein Cell Biology Canadian Institutes of Health Research 1997 – 2002

Amira Klip Cell Biology Canadian Institutes of Health Research 1999 – 2004

Gideon Koren Population Health Sciences Canadian Institutes of Health Research 2000 – 2005

Marlene Rabinovitch Cardiovascular Research Canadian Institutes of Health Research 2000 – 2005

Lap-Chee Tsui Genetics & Genomic Biology Canadian Institutes of Health Research 2000 – 2005

Investigators (Scientists)

program grantor term

Maureen Andrew Population Health Sciences Heart and Stroke Foundation of Ontario 2000 – 2002

Gabrielle Boulianne Developmental Biology Canadian Institutes of Health Research 2000 – 2005

John Chamberlain Infection, Immunity, Injury & Repair Ontario HIV Treatment Network 2000 – 2005

Jayne Danska Developmental Biology National Cancer Institute of Canada 1995 – 2001

John Dick Cancer & Blood Canadian Institutes of Health Research 1996 – 2001

Julie Forman-Kay Structural Biology & Biochemistry Canadian Institutes of Health Research 2000 – 2005

Cynthia Guidos Developmental Biology Canadian Institutes of Health Research 1997 – 2002

Aleksander Hinek Cardiovascular Research Heart and Stroke Foundation of Ontario 1999 – 2004

Chi-chung Hui Developmental Biology National Cancer Institute of Canada 1999 – 2005

Susanna Lewis Genetics & Genomic Biology National Cancer Institute of Canada 1996 – 2002

David Malkin Cancer & Blood National Cancer Institute of Canada 1997 – 2003

Jayne McGlade Cell Biology National Cancer Institute of Canada 1999 – 2005

Nancy Olivieri Cancer & Blood Canadian Institutes of Health Research 1996 – 2001

Daniela Rotin Cell Biology Canadian Institutes of Health Research 1999 – 2004

James Rutka Brain & Behaviour Canadian Institutes of Health Research 1999 – 2004

Michael Salter Brain & Behaviour Canadian Institutes of Health Research 1998 – 2003

Rosemary Tannock Brain & Behaviour Canadian Institutes of Health Research 1998 – 2003

William Trimble Cell Biology Canadian Institutes of Health Research 2000 – 2005

James Wright Population Health Sciences Canadian Institutes of Health Research 1998 – 2003

New Investigators (Scholarships)

program grantor term

Anthony Chan Integrative Biology Heart and Stroke Foundation Canada 1999 – 2004

Gabrielle deVeber Population Health Sciences Heart and Stroke Foundation of Ontario 1998 – 2001

Paul Dick Population Health Sciences Ministry of Health and Long-Term Care 1999 – 2004

Sean Egan Developmental Biology Canadian Institutes of Health Research 1996 – 2001

Brian Feldman* Population Health Sciences Ministry of Health and Long-Term Care 1996 – 2003

Gregory Hannigan Cell Biology Canadian Institutes of Health Research 1997 – 2002

Jim Hu Lung Biology Canadian Cystic Fibrosis Foundation 2000 – 2003

Shinya Ito Integrative Biology PMAC Health Research Foundation/

Canadian Institutes of Health Research 1997 – 2002

Zhengping Jia Brain & Behaviour Canadian Institutes of Health Research 1999 – 2004

Nicola Jones Infection, Immunity, Injury & Repair American Digestive Health Foundation 2000 – 2003

Gergely Lukacs Cell Biology Canadian Institutes of Health Research 1995 – 2000

Lesley Mitchell Population Health Sciences Canadian Institutes of Health Research 1999 – 2004

Christopher Pearson Genetics & Genomic Biology Canadian Institutes of Health Research 1999 – 2004

Stephen Scherer Genetics & Genomic Biology Canadian Institutes of Health Research 1998 – 2003

Bonnie Stevens* Population Health Sciences Ministry of Health and Long-Term Care 1993 – 2001

Lu-Yang Wang Brain & Behaviour Canadian Institutes of Health Research 1998 – 2003

Yu Tian Wang Brain & Behaviour Heart and Stroke Foundation Canada 1996 – 2001

Rae Yeung Cancer & Blood The Arthritis Society 1997 – 2001

*University of Toronto

Clinician Scientists

program grantor term

Ab Guha* Cancer & Blood Canadian Institutes of Health Research 1999 – 2002

* University of Toronto

Canada Research Chairs Tier I

program grantor term

Mark Henkelman* Integrative Biology Canadian Institutes of Health Research 2001 – 2007

Martin Post Lung Biology Canadian Institutes of Health Research 2001 – 2007

Brian Robinson Metabolism Canadian Institutes of Health Research 2001 – 2007

Philip Sherman Infection, Immunity, Injury & Repair Canadian Institutes of Health Research 2001 – 2007

* The Hospital for Sick Children and Sunnybrook and Women’s College Health Sciences Centre

Canada Research Chairs Tier II

program grantor term

Benjamin Alman Developmental Biology Canadian Institutes of Health Research 2001 – 2005

Régis Pomès Structural Biology & Biochemistry Canadian Institutes of Health Research 2001 – 2005

awards $3,217,685

fringe benefits $281,741

total awarded $3,499,426

Funding from external agencies listed by grantor

agency project award total %

Abbott Laboratories, Limited 94,658 — 94,658 0.16

Agouron Pharmaceuticals, Inc. 30,670 —— 30,670 0.05

Alberta Heritage Foundation for Medical Research 2,000 28,417 30,417 0.05

American Association for the Study of Liver Diseases — 73,660 73,660 0.12

American Brain Tumor Association 72,515 — 72,515 0.12

American College of Radiology 22,001 — 22,001 0.04

American Digestive Health Foundation — 75,000 75,000 0.12

American Health Assistance Foundation 147,870 — 147,870 0.25

Amgen Inc. 4,000 — 4,000 0.01

Angiotech Pharmaceuticals, Inc. 64,000 — 64,000 0.11

Apotex Research Inc. 32,375 — 32,375 0.05

Associated Medical Services, Inc. 15,000 — 15,000 0.02

Association of Canadian Medical Colleges 14,320 — 14,320 0.02

ASTA Medica Aktiengesellschaft 53,879 — 53,879 0.09

AstraZeneca Canada Inc. 30,600 — 30,600 0.05

Ataxia-Telangiectasia Medical Research Foundation 40,991 — 40,991 0.07

Aventis Behring Canada Inc. 59,788 — 59,788 0.10

Avocet Medical Inc. 7,510 — 7,510 0.01

Banting & Best Diabetes Centre 25,950 33,561 59,511 0.10

Baxter Healthcare Corporation 24,488 — 24,488 0.04

Bayer Inc. 192,054 — 192,054 0.32

Bayer Institute for Health Care Communication 24,038 — 24,038 0.04

Biochem Pharma and GlaxoWellcome 30,000 — 30,000 0.05

Biorthex Inc. 15,878 — 15,878 0.03

Bloorview Childrens Hospital Foundation 410,439 — 410,439 0.68

Bracco Diagnostic Canada 8,750 — 8,750 0.01

Brainchild 24,942 — 24,942 0.04

Bristol-Myers Squibb Canada Inc. 5,000 — 5,000 0.01

Canada Foundation for Innovation 2,930,925 — 2,930,925 4.88

Canadian Arthritis Network 95,000 16,000 111,000 0.18

Canadian Association of Gastroenterology 27,500 40,000 67,500 0.11

Canadian Cystic Fibrosis Foundation 1,702,714 410,738 2,113,452 3.52

Canadian Diabetes Association 165,116 33,000 198,116 0.33

Canadian Foundation for Dietetic Research 5,358 — 5,358 0.01

Canadian Foundation for Woman’s Health 19,250 — 19,250 0.03

Canadian Genetic Diseases Network 604,679 12,000 616,679 1.03

Canadian HIV Trials Network 5,000 40,000 45,000 0.07

Canadian Institutes of Health Research 13,595,363 3,731,798 17,327,161 28.85

Canadian Lung Association 4,500 54,030 58,530 0.10

Canadian Paediatric Society 46,842 — 46,842 0.08

Canadian Stroke Network 93,000 — 93,000 0.15

Cangene Corporation 22,200 — 22,200 0.04

Centers for Disease Control and Prevention 165,111 — 165,111 0.27

Children’s and Women’s Health Centre of British Columbia 7,500 — 7,500 0.01

Crohn’s & Colitis Foundation of Canada 77,987 64,000 141,987 0.24

Cure Autism Now Foundation 52,447 — 52,447 0.09

Dade Behring Inc. 35,778 — 35,778 0.06

Digestive Care, Inc. 26,697 — 26,697 0.04

Duchesnay Inc. 227,500 — 227,500 0.38

Eli Lilly Canada Inc. 164,410 — 164,410 0.27

Fragile X Research Foundation of Canada — 30,000 30,000 0.05

Fujisawa Canada Inc. 18,206 — 18,206 0.03

Fujisawa Healthcare, Inc. 15,911 — 15,911 0.03

GlaxoSmithKline 33,000 — 33,000 0.05

Health Canada 116,500 — 116,500 0.19

Heart and Stroke Foundation Canada — 234,120 234,120 0.39

Heart and Stroke Foundation of Ontario 2,016,556 226,044 2,242,600 3.73

Howard Hughes Medical Institute 300,381 — 300,381 0.50

Human Frontier Science Program 72,925 — 72,925 0.12

Immunex Corporation 12,467 — 12,467 0.02

Institut Rosell, Lallemand Inc. 36,755 — 36,755 0.06

Inveresk Research 35,000 — 35,000 0.06

Issho Genki International Limited 48,375 — 48,375 0.08

Janssen-Ortho Inc. 20,000 — 20,000 0.03

John Hopkins University 11,460 — 11,460 0.02

Johnson & Johnson Medical Products 6,250 — 6,250 0.01

Juvenile Diabetes Foundation International 535,152 — 535,152 0.89

KidsAction Research — 41,060 41,060 0.07

Kinetek Pharmaceuticals Inc. 73,385 — 73,385 0.12

Knoll Pharma Inc. 8,100 — 8,100 0.01

Leo Pharma Inc. 46,018 — 46,018 0.08

Leukemia Research Fund of Canada 52,500 35,000 87,500 0.15

Lotte & John Hecht Memorial Foundation 50,000 — 50,000 0.08

LymphoSign Inc. 345,000 — 345,000 0.57

2000Ð2001 external funders

Research Institute

101


Annual Report 2000-2001 2000Ð2001 external funders

102

agency

Macula Vision Research Foundation

project

121,680

award


total

121,680

%

0.20

March of Dimes Birth Defects Foundation 280,715 — 280,715 0.47

Materials and Manufacturing Ontario 40,125 — 40,125 0.07

Medeva Pharmaceuticals Inc. 14,927 — 14,927 0.02

MedImmune, Inc. 9,057 — 9,057 0.02

Merck Frosst Canada & Co. 4,600 — 4,600 0.01

Ministry of Community and Social Services 407,440 — 407,440 0.68

Ministry of Health and Long-Term Care 424,187 164,623 588,810 0.98

Miscellaneous 529,394 7,697 537,091 0.89

Multiple Sclerosis Society of Canada 159,310 69,854 229,164 0.38

Muscular Dystrophy Association, Inc. 135,000 — 135,000 0.22

National Cancer Institute of Canada 3,129,650 562,731 3,692,381 6.15

National Institutes of Health 3,806,741 — 3,806,741 6.34

National Sanatorium Association 82,000 — 82,000 0.14

Natural Sciences and Engineering Research Council of Canada 294,687 — 294,687 0.49

Network of Centres of Excellence - MITACS 25,000 — 25,000 0.04

Novartis Farmaceutica S.A. 86,500 — 86,500 0.14

Novartis Pharmaceuticals Canada Inc. 105,000 — 105,000 0.17

Ontario Federation for Cerebral Palsy — 50,000 50,000 0.08

Ontario HIV Treatment Network 348,169 67,500 415,669 0.69

Ontario Innovation Trust 3,766,568 — 3,766,568 6.27

Ontario Lupus Association 25,000 — 25,000 0.04

Ontario Mental Health Foundation 330,598 — 330,598 0.55

Ontario Neurotrauma Foundation 175,229 85,000 260,229 0.43

Ontario Research and Development Challenge Fund 4,728,048 — 4,728,048 7.87

Ontario Respiratory Care Society/Ontario Lung Association 12,500 — 12,500 0.02

Ontario Thoracic Society 21,000 5,000 26,000 0.04

Ontario Veterinary Medical Association 32,500 — 32,500 0.05

Organ Donation Ontario 12,613 — 12,613 0.02

Organon Canada Ltd. 5,500 — 5,500 0.01

Orthopaedic Research and Education Foundation 43,821 — 43,821 0.07

Paediatric Consultants 49,027 — 49,027 0.08

Pediatric Oncology Group of Ontario 58,790 — 58,790 0.10

Periodontix, Inc. 24,975 — 24,975 0.04

Pfizer Canada Inc. 390,493 — 390,493 0.65

Pfizer Inc. 150,354 — 150,354 0.25

Pharmacia Canada Inc. 70,000 — 70,000 0.12

Plastic Surgery Educational Foundation 7,390 — 7,390 0.01

PMAC Health Research Foundation — 34,522 34,522 0.06

Premier’s Research Excellence Award 589,668 — 589,668 0.98

Protein Engineering Network of Centres of Excellence 44,187 — 44,187 0.07

Psychiatry Endowment Fund 133,001 — 133,001 0.22

Purdue Frederick 104,377 — 104,377 0.17

Ronald McDonald House Charities 11,485 — 11,485 0.02

Schering Canada Inc. 37,223 — 37,223 0.06

Select Therapeutics (Canada) Inc. 23,000 — 23,000 0.04

Shwachman Diamond Syndrome Canada Inc. 60,877 — 60,877 0.10

SmithKline Beecham Pharma 81,495 — 81,495 0.14

Smokeless Tobacco Research Council, Inc. 77,643 — 77,643 0.13

Social Sciences and Humanities Research Council of Canada 185,000 — 185,000 0.31

Synthes (Canada) Ltd. 35,000 — 35,000 0.06

Synthes (U.S.A.) 19,984 — 19,984 0.03

SynX Pharma Inc. 23,541 — 23,541 0.04

The Arthritis Society 163,512 45,000 208,512 0.35

The Cancer Research Society Inc. 94,000 — 94,000 0.16

The CSHP Research and Education Foundation 10,120 — 10,120 0.02

The EJLB Foundation 200,000 — 200,000 0.33

The Hearing Foundation of Canada 31,160 — 31,160 0.05

The Hospital for Sick Children Foundation* 3,951,373 — 3,951,373 6.58

The International Development Research Centre 62,400 — 62,400 0.10

The Kidney Foundation of Canada 160,746 90,000 250,746 0.42

The Multiple Sclerosis Scientific Research Foundation

The National Alliance for Research

25,720 — 25,720 0.04

on Schizophrenia and Depression — 45,209 45,209 0.08

The PATH Foundation of Canada 13,098 — 13,098 0.02

The Physicians’ Services Incorporated Foundation 229,400 — 229,400 0.38

The STARBRIGHT Foundation 7,500 — 7,500 0.01

Toronto Professional Fire Fighter’s Association 10,000 — 10,000 0.02

Transition Therapeutics, Inc. 155,725 — 155,725 0.26

University Medical Discoveries Inc. 25,000 — 25,000 0.04

University of Michigan Medical School 11,744 — 11,744 0.02

University of Toronto 275,486 1,500,000 + 1,775,486 2.96

52,144,587 7,905,564 60,050,151 100.00

* Donations and income from endowment funds administered through The Hospital for Sick Children Foundation and transferred

to the Research Institute to support research activities.

+ Income from The Hospital for Sick Children Foundation Graduate Student Awards endowment held at the University of Toronto.

The Association of Research

Assistants and Technologists

was established at The Hospital

for Sick Children to enhance

communication between

laboratories and other areas

of the Research Institute.

Executive

Monica Doedens, Chair

Brenda Knie

Richard Mount

Margaret Miller

Peter Pasceri

Adolescent Medicine

Cynthia Kirsh

Richard Snow

Biomedical Physics

Rachel Derrane

Brain & Behaviour Research

Jenny Archibald

Patricia Arseneau

Anne-Claude Bedard

Martin Bissessar

Stacey Bloom

Tally Bodenstein-Kales

Joel Brody

Shirley Chen

Hillary Christensen

Penny Corkum

Jillian Dejean

Maria Depalma

Mary Desrochers

Lisa Fiksenbaum

Ian Frijters

Jeff Gingrich

Christine Graziosi

Janice Hicks

Min-na Hockenberry

Shameela Hoosen-Shakeel

Mary Hum

Jennifer Janes

Jason Kotsopoulos

Stephanie Lane

Chun-che Dick Liu

Mariko Lui

Rhonda Martinussen

Richard Mount

Sandra Newton

Victoria Orekhovsky

Caroline Rorcadin

Angeline Sarabura

Shahira Shokralla

Julie Solomon

Karen Steinbach

Jo-Ann Lee Stewart

Aina Tilups

Margaret Wilkinson

David Wong

Danuta Zylka

Cancer & Blood Research

Susan Chilton-MacNeill

Brenda Cohen

Ursula Cymerman

Monica Doedens

Pasha Emadi-Konjin

Graciela Flock

Ildiko Grandal

Liping Han

Lijing He

Sherrilynn Hubbard

Cindy Hui Zhang

Jodi Lees

Chung Yee Leung-Hagesteijn

Eugene Lui

Soma Mondal

Steven Mortin-Toth

Izabela Naruszewicz

Martin Nemec

Pearl Rimer

L.E. Sexsmith

Peizhu Sun

Bonjan Tadic

Sonia Vera

Hong Wang

Wei Wang

Urszula Wojtyra

Oliver Yeung

Cindy Zhang

Cardiology

Kourosh Dinyari

Sandra Singhroy

Shufang Zhao

Cardiovascular Research

Roberto Diaz

Bonnie Isacovics

Nilo Kaviani

Stephanie Langlois

Guo Mao

Lawrence Ng

Ida Samii

Mingda Shi

Eva Sitarz

Gordana Svajger

Xuejun Wu

John Wylie

Ewa Zielinska

Cell Biology

Donna Berry

Natasha Coady-Osberg

Monideepa Choudhury

Richard Collins

Soad Fahim

Chris Fladd

Wendy Furuya

Ling Huan

Robert Kinach

Chen Kong

Zhi Liu

John Gregory Marshall

Yanchun Wang

Michael Woodside

Hong Xie

Child Development Centre

Patrycja Krzeminska

Elizabeth Thompson-Hahne

Critical Care

Helena Frndova

Developmental Biology

Nizar Batada

Ian Clarke

Haddas Groshain

Dianne Holland

Aihua Huang

James Hughes

Angelo Karaiskakis

Gisele Knowles

Hua Luo

Margaret Miller

Peter Pasceri

Lynda Ploder

Tanya Sukonnik

Vijitha Thanabalsingham

Diana Vandehoef

Danka Vidgen

Yanping Wang

Linda Wei

Sandy Yu

Yunkai Yu

Sally Zhang

Mary Zhang-Zhao

Anguo Zhong

Endocrinology

Maria Dekker

Chunying Yu

General Surgery

Michelle Kushida

Lydia Mai

Genetics & Genomic

Biology

Noa Alon

Doreen Anderson

Xinli Bai

Catherine Chan

Iris Fang

Yan Fei

Nadia Feroz

Jo-Anne Herbrick

Zhizhou Hu

Jun-rong Huang

Association of Research Assistants and Technologists

Research Institute

103


Association of Research Assistants and Technologists

Annual Report 2000-2001

104

Subha Indrarajah

Cecilia Kasmara

Jean Kawasoe

Catherine Li

Martin Li

Xiaobin Li

Lili Liu

Patricia Lu

Xiaoli Lu

Monique Meloche

Jodi Morrison

Nicole Newhook

Kerrie Nichol

Van Nguyen

Raymond Poon

Margaret Rozenberg

Jennifer Skaug

Miki Susic

Jeanette Wilkins

Eddy Wong

Sharon Wong

Yuhuan Xia

Felix Young

Xiao-Wei Yuan

GI/Nutrition

Esther Galindo

Kathene Johnson-Henry

Ana Piekarz

Infection, Immunity,

Injury & Repair Research

Karen Aitken

Enrico Arpaia

Beth Binnington-Boyd

Hargit Dadi

Dale DeMatteo

Cathy Denhollander

Thomas Grunberger

Anastazia Jager

Puviindran Dadesan

Anita Nutikka

Ke Sheng Tao

Wilma Vanek

Jennifer Zhang

Infectious Diseases

Tanya Degazio-Thibodeau

Xiaoyi Li

Karen Siu

Integrative Biology

Satti Beharry

Vicki Cook

Wan Ip

Annie Aihua Lin

Danuta Markiewicz

Mahroukh Rafii

Vaishali Raval

Huai Xu

Laboratory Animal

Services

Crocetta Accardi

Marvin Estrada

France Fortin

Angie Griffin

Debbie Holsmer

Gregory Madeley

Christine Platzer

Maria Robles

Dieter Schmidt

Nicholas Smith

Sarah Timms

Lung Biology

Rosetta Belcastro-Taylor

Elizabeth Bienkowski

Judy Cabacungan

Tanya Freywald

Xiao Wen Fu

Stephane Gagnon

Vicky Hannam

Kimberly Kalata

Maciej Kuliszewski

Jenny Kwong

Lisa Drowsky

Jonathan Plumb

Bijan Rafii

Brent Steer

Irene Tseu

Anan Wang

Jinxia Wang

Yanxia Wen

Veronica Wong

Yuan Hong Wu

Metabolism

Frank Cui

Krystyna Figurska

Anne-Marie Lamhonwah

Valeriy Levandovskiy

Tomoko Myint-Talwalkar

Claudia Schauer

Cathy Yang

Suyun Yang

Microbiology

Danuta Kovach

Neonatology

Andrea Downie

Neurology

Helene Anne France Chevalier

Bonnie MacKinnon

Yu Zhang

Ophthalmology

Kim Smith

Paediatric Medicine

Ann Foster

Paediatrics

Barbara Shea

Pathology

Sue Omar

Jie Pan

Peter Wilson

Paediatric Laboratory Medicine

Liping Han

Kit Leung

Population Health Sciences

Maria Dinyari

Suzanne Cadarette

Nicole Cohen

Trish Domi

Sandra Donaldson

Annie Dupuis

Samia Guindy-Wasfy

Tatyana Karaskov

Brenda Knie

Chryssa Koulis

Sandra Lecce

Sherry Maharaj

Irena Nulman

Sheila Purkiss

Lina Santaguida

Stephanie Wiesenthal

Research Administration

Jacob Brener

Barbara Kellam

Respiratory Medicine

Bernard Ho

Structural Biology

& Biochemistry

Homa Ashrafpour

Rick Bagshaw

Sherilyn Bell

Chandra Boon

Elene Elisseeva

Donna Francis

Miroslawa Glibowicka

Reynaldo Interior

Shashikant Joshi

Amy Leung

Lingya Liao

Hong Lin

Teresa Miani

Suree Narindrasorasak

Godha Rangaraj

Mohan Sarkar

Chiew Tan

Stephen Van Iderstine

Huimin Wang

Nam Wang

Fei Xiong

Patrick Yip

Sunqu Zhang