1st International Conference Models of Human Diseases oral presentations abstracts feature recent findings in development or emplyment of various models of diseases to advance biomedical research.

1. University of Toronto
Faculty of Medicine
Department of Laboratory Medicine and Pathobiology
“Better models for better drugs!”
First International Annual
Conference sponsored by CIHR
Models of Human Diseases
Organizing team Date: June 29th, 2010
Dr. Lorelei Silverman, co-chair, CIHR grant recipient
Dr. Rosalind Silverman, co-chair, CIHR grant recipient Time: 8:30 am-7 pm
Team leaders Location: Medical Sciences Building, 1 King’s College
Dr. Ruth Warre, communication, newsletter
Dr. Hamid Raziee, poster coordinator/database coordinator
Circle, MacLeod Auditorium
Hassan Bilal, treasurer
Gazhal Fazli, fundraising
Nada Hussain, secretary
Judges:
Dr. Mark Gertner, Dr. Peter Sabatini (online), Dr. Guangpei Hou, Dr. Abbas
Karbasian (online), Dr. Antonio Rocca, Dr. Lloyd Berger
Volunteers: Rodin, The Thinker
Morisson Steel, Ehsan Movasaghi, Nardeen Kodous, Anastasya Sivkova,
Swati Agnihotri, Mary Yang, Lisa Tran, Isabella Au, Karen Britto, Ashley
Ross, Josh Lopes, Lucy Duan, Mark Wan, David Wang, Sameena Vadivelu,
Dhruva Thaker, Ami Patel, Chenthila Nagamuthu, Mengxi Dong, Ayesha
Siddiqua, Marzena Serwin,

2. PROGRAM
8:30 am Registration, Refreshments, Exhibitor displays, Poster set-up
9:00 am Dr. Catharine Whiteside, Dean of the Faculty of Medicine, U of Toronto, Welcome message Many thanks to the institutions, companies and individuals who made the
Dr. Rosalind Silverman and Dr. Lorelei Silverman, University of Toronto, Introduction 1st International Annual Conference on Models of Diseases possible due to their
9:15 am Dr. Lee Adamson -Keynote speaker, Director, Mouse Physiology Core, Centre for Modeling
Human Disease; Principal Investigator, Samuel Lunenfeld Research Institute of Mount Sinai
generous donations and support:
Hospital; Professor, Obstetrics and Gynaecology, University of Toronto.
A decade of ENU mutagenesis at the Centre for Modeling Human Disease: Successes and Canadian Institute of Health Research, Genetics Institute of Genetics for awarding us
lessons learned
10:00 am Dr. Michelle Bendek, Professor Laboratory Medicine and Pathobiology, U of Toronto
a Meetings, Planning, and Dissemination grant
Using a mouse model to study inflammation, fibrosis and calcification of atherosclerosis Dr. Milton Charlton and Dr. Michelle Bendek, our supervisors
10:30 am Dr. Szcezepan Baran, President and COO, Veterinary Bioscience Institute, USA Dr. Catharine Whiteside, Dr. Richard Hegele, and Dr. Avrum Gotlieb for their support
Rodent laparoscopy refinement for rodent model development of renal, testicular and Dr. Roger Lew, Dr. Ronald Pearlman, and Dr. Andrew Wilde
All the outstanding speakers of this conferernce
hepatic laparoscopic implantation of neoplastic cells (dedicated to the memory of Ms.
Evelyn Lazar)
11:00 am Coffee break, Refreshments, Exhibitor displays Dr. Szczepan Baran and the Vterinary Bioscience Institute for hosting posters
11:15 am Non-Rodent Models of Diseases Cedarlane for sponsoring our website www.nabmc.info
Dr. Milton Charlton, Professor, Department of Physiology, University of Toronto, Toronto
Squid, Frog, Crayfish, and Drosophila models in Neuroscience
Study Advantage for IT and database consultation
11:45 am Dr. Zhong-Ping Feng, Associate Professor, Department of Physiology, University of Toronto, Abcam for sponsoring the best posters awards
Lymnaea stagnalis, a multitalented model in integrative neurophysiology Kent Scinetific, Charles River, Fermentas, Roche, Ultident for sponsoring loot bags
12:00 am Dr. Thomas Koch, Adjunct Professor, Department of Biomedical Sciences, Ontario University staff for their advice, suggestions, or help during conference preparation
San Diego Instruments, Mandel, and Charles River for sponsoring seminar series
Veterinary College, University of Guelph
Equine umbilical cord blood stem cell and tissue engineering based therapies using the
horse as a pre-clinical animal model of orthopedic problems ALN magazine, Elsevier, ScientificWorld Journal, and Frontiers in Neuroscience
12:15 pm Lunch, Exhibitor displays/ Poster viewing and judging Journal for future publications of abstracts Falk and Falk attorneys for consultation of
1:15 pm Dr. Richard Hegele, Chair Department of Laboratory Medicine and Pathobiology, University
of Toronto- Afternoon session opening message
US affiliations
1:20 pm Dr. John Wallace, Director, Farncombe Family Digestive Health Research Institute,
McMaster University, Hamilton, Canada
Studying human GI inflammation and ulceration using rodent model
1:50 pm Dr. Jeffrey Henderson, Associate Professor, Leslie Dan Faculty of Pharmacy, U of Toronto,
Director, Murine Imaging and Histology Facility
Development of interactive surgical and multimodal atlases of the mouse CNS: Toward
Integrative Neuroanatomic Measures
2:20 pm Dr. Jack Uetrecht, Professor, Leslie Dan Faculty of Pharmacy, U. of Toronto
Animal models to understand and ultimately prevent idiosyncratic drug reactions
2:50 pm Dr. David Rollo, Professor, McMaster University, Hamilton, Canada
Aging and development of successful dietary interventions: Lessons from transgenic growth
hormone mice that express a progeroid syndrome of accelerated aging
3:20 pm Coffee break, Refreshments, Exhibitor displays
3:35 pm Dr. Adam Karpf, Roswell Park Cancer Institute, Department of Pharmacology and
Therapeutics, Buffalo, USA
DNA methylation in a murine prostate cancer model
4:05 pm Dr. Levon Khachigian, Director, UNSW Centre for Vascular Research, University of New
South Wales, Sydney, Australia
Immediate-early genes as master regulators in a wide range of vascular disorders
5:00 pm Non-Rodent Models of Diseases
Dr. Joseph Culotti, Principal Investigator, Samuel Lunenfeld Research Institute, Toronto
C. elegans as a model for gene discovery in the development and function of the nervous
system
5:15 pm Dr. Ronald Pearlman, University Professor Emeritus and Senior Scholar, Department of
Biology. York University, Toronto
The Ciliate Protozoan Tetrahymena thermophila as an important animal model organism
5:30 pm Dr. Corey Nislow, Assistant Professor, Banting and Best Department of Medical Research,
Toronto
Gene-dose assays for drug discovery in yeast and man
5:45 pm Dr. Maurice Ringuette, Professor, Cell and Systems Biology Department, U. of Toronto
The use of multiple model organisms to reveal the complex structural and regulatory
contributions of an extracellular matrix protein during normal and pathological development
6:00 pm Dr. Joffre Mercier, Professor, Department of Biological Sciences, Brock University, Associate Dean,
Faculty of Math & Science
Drosophila as a model system for studying neuropeptides and endocrine regulation
6:15 pm Closing remarks and gift certificate draw
6:30 pm Awards reception Roche Fermentas Ultident
7:15 pm Dinner with the speakers (by invitation only).5
Falk and Falk attorneys
Immigration Law

3. Dr. A. Joffre Mercier
Professor, Department of
Biological Sciences,
Brock University,
Associate Dean,
Faculty of Math &
Science
Drosophila as a model system for studying Dr. Lorelei Silverman Dr. Rosalind Silverman
Welcome to the First International
neuropeptides and endocrine regulation Annual Conference on Models of
Neuropeptides are oligopeptides that can act as Human Diseases! This initiative springs
neurotransmitters, hormones and modulators. Approximately fifty from our journey through the
neuropeptides have been identified in the human central nervous biomedical field from academia to
system, and many hundred have been identified in vertebrate biotech, to consulting and clinical
and invertebrate species. Although it is known that levels of research and back to academia and our
neuropeptides are altered in diseases such as Huntington’s belief that global scientific exchange
Disease and Alzheimer’s Disease, a thorough understanding of can accelerate drug development. Once
clinical conditions requires more complete understanding of how the CIHR awarded us a grant to
neuropeptides mediate physiological responses and modulate organize this conference we had 30 days
behaviour through their actions at systemic, cellular and sub- to turn it into reality. Here is the recipe:
cellular levels. Drosophila melanogaster provides numerous an amazing team of volunteers with the
advantages as a model system for such studies. Every muscle right proportion of dreamers and doers,
fiber in the larvae has been identified, and the innervation of enthusiasts and realists. Add deans of
each fiber is known, making it possible to study synaptic universities and high school students,
interactions between identified cells using electrophysiological supervisors and graduate and
and optical methods. Some of these synapses release undergraduate students from around the
neuropeptides, and some are modulated by neuropeptides. globe, administrative secretaries and
Since the Drosophila genome has been cloned and sequenced, foreign trained researchers, clinicians,
mutant and transgenic fly lines have become available for biotech and pharma scientist, policy
studying the roles of G-protein coupled receptors and makers, postoctoral fellows, life science
intracellular messengers in mediating peptide-induced effects on companies, lawyers, and advocacy
chemical synapses, muscle contraction and behaviour. groups.
We wish you a stimulating day of
science!

4. Greetings for The 1st International Dr. Maurice Ringuette
Annual Conference of Models of Professor, Cell and Systems
Human Diseases
On behalf of the Faculty of
Biology Department,
Medicine, I am pleased to University of Toronto,
enthusiastically congratulate the Toronto
organizers of the First International
Annual Conference of Models of
Human Disease on this great
achievement. To Drs. Lorelei and The use of multiple model organisms to reveal the
Rosalind Silverman and their
faculty supervisors Professors
complex structural and regulatory contributions of
Milton Charlton and Michelle Bendeck, many thanks for an extracellular matrix protein during normal and
your creative development of this outstanding project. pathological development
Shortly after fertilization, multicellular organisms synthesize and secrete a complex mixture
Sponsored by the CIHR and many other contributors, this of structurally and functionally diverse extracellular matrix (ECM) molecules. In addition to
conference has attracted investigators and students from acting as scaffolding for the organization and stability of tissues, ECM molecules regulate
cell survival and behavior. We have been using a variety of model organisms to decipher
across the globe who share significant interest in animal the precise morphogenetic contributions of SPARC (Secreted Protein, Acidic, Rich in
Cysteine) during normal and pathological development. SPARC is a small, collagen- and
models of human disease. calcium-binding “matricellular” glycoprotein that is expressed at high levels in tissue
In the era of personalized medicine, we look to the undergoing morphogenesis, remodeling or wound repair. SPARC has also attracted
considerable interest due to its altered expression during progression of diverse diseases
translation of molecular and cellular mechanisms of disease (e.g. fibrosis and cancer). Our studies with the cnidarian starlet sea anemone
into innovative bedside applications. The necessary Nematostella vectensis indicate that the collagen-binding domain of SPARC is conserved
throughout metazoan evolution. We have used the African clawed frog Xenopus laevis to
intermediate step is the study of animal models in which the demonstrate a critical requirement for SPARC during post-gastrula development.
manipulation of genes, proteins, cells and systems to fully Specifically, SPARC, directly or indirectly, promotes cell-cell adhesion which is required for
the maintenance of tissue integrity during organogenesis. Using the powerful molecular
understand how human diseases are generated. This and genetic tools available for the fruit fly Drosophila melanogaster, our data indicate that
approach enables the testing of new diagnostic and SPARC is expressed at high levels in the fat body, an organ compared functionally to
vertebrate adipose tissue and liver that serves as a major organ for energy storage and
therapeutic interventions that provide important new metabolism. Our data indicate that the fat body is absent during larval development in
Sparc-null flies. SPARC has been suggested to have anti-tumour effects on ovarian
directions in health care. May I wish all the participants cancer progression, in part due to its demonstrated ability to inhibit cell proliferation and
success in networking and establishing new opportunities for migration. We have recently shown using a chick chorioallantoic membrane assay that a
mimetic peptide corresponding to the most evolutionary conserved domain of SPARC
collaboration during this conference. I hope you also enjoy prevents endothelial cell branching angiogenesis. We plan to use this in vivo assay in
Toronto and our wonderful University of Toronto campus. combination with a mouse syngeneic model of ovarian cancer to better understand the
anti-tumor activity of SPARC during ovarian cancer progression and metastasis. Each of
Dr. Catharine Whiteside, MD, PhD, FRCPC, FCAHS the above models has offered unique insight into this ECM glycoprotein with complex
Dean, Faculty of Medicine, Profesor of Medicine spatiotemporal distributions during embryogenesis and whose expression is altered in
several disease states.
University of Toronto

5. Dr. Corey Nislow Greetings for 1stInternational
Assistant Professor, Conference of Models of Human
Banting and Best Diseases
Department of Medical On behalf of the Department of Laboratory
Research, University of Medicine and Pathobiology of the University
of Toronto, I would like to extend a warm
Toronto welcome to all attendees of the First
International Annual Conference of Models
of Human Diseases. The origins of this
International Conference can be attributed
to the tireless efforts of two sisters, Drs.
Gene-dose assays for drug discovery in yeast Lorelei and Rosalind Silverman, who work,
and man respectively, as a Research Associate at the University of Toronto in the
My lab is interested in understanding the interaction of Department of Physiology (Supervisor: Dr. Milton Charlton) and as a Post-
small molecules with their protein targets and target doctoral fellow, Department of Laboratory Medicine and Pathobiology
(Supervisor: Dr. Michelle Bendeck). Earlier this year, Lorelei and Rosalind
pathways. To accomplish this, we use comprehensive
organized what has become a popular and highly successful seminar series
collections of cells in which the gene dosage is
on Animal Models of Human Disease at the University of Toronto, and for
systematically altered (decreased or increased). We have this International Conference the scope has been extended to also include
utilized the Yeast Knock Out collection (YKO) and cellular models.
combined it with a collection of yeast overexpressing each
gene to screen thousands of bioactive small molecules The Canadian Institutes of Health Research, the major federal
genome-wide, identifying many novel gene-drug funding body of biomedical research in Canada, has provided
interactions. More recently we have expanded the scope of financial support for this International Conference in the form of a
these gene-dose screens to other organisms and genomes. competitive award, and the engagement of additional sponsors is a
For example, we have successfully screened the human testament to the broad relevance and potential impact of this area
ORFeome, expressed in yeast, with FDA approved of research. The ability for interested individuals from around the
compounds and have identified several known and novel world to engage in information and knowledge exchange in models of
human disease is timely. People at all levels of expertise and
interactions. In collaboration with Jason Moffat’s laboratory,
experience stand to benefit from participating in the discourse and
we've initiated a large-scale effort to translate these gene- exploring new opportunities to form or strengthen research
dose screens to mammalian cells using pools of cells collaborations.
infected with lentiviral-encoded shRNAs and human OFRs. Sincerest best wishes for an exciting, stimulating and successful meeting.
I will present several compelling drug-target interactions
that have been uncovered using a combination of these
Richard G. Hegele, MD, FRCPC, PhD
gene-dose screens as well as provide an overview of our Professor and Chair
efforts to develop novel microarray and next-generation Department of Laboratory Medicine and Pathobiology
sequencing technologies to accelerate the tempo of these University of Toronto
chemogenomic assays.

6. Dr. Lee Adamson Dr. Ronald Pearlman
Director, Mouse Physiology Core, University Professor
Centre for Modeling Human
Emeritus and Senior
Disease; Principal Investigator,
Samuel Lunenfeld Research
Scholar, Department of
Institute of Mount Sinai Hospital; Biology, York University,
Professor, Obstetrics and Toronto
Gynaecology, U. of Toronto
A decade of ENU mutagenesis at the Centre for The Ciliate Protozoan Tetrahymena thermophila as
Modeling Human Disease: Successes and an important animal model organism
The ciliate protozoan Tetrahymena thermophila belongs to the Alveolates, a major
lessons learned evolutionary branch of eukaryotic protists. T. thermophila is a microbial model organism for
a wide variety of research disciplines. In addition to its proven importance as a model
Toronto’s Centre for Modeling Human Disease (CMHD) system for discovering fundamental principles of eukaryotic biology, it is the most
used dominant ENU-mutagenesis to generate new experimentally amenable member of the Alveolates and of the evolutionarily diverse ciliate
species that colonize worldwide niches as free-living organisms, parasites, and mutualistic
mouse models of disease from 2000-2010. The talk will symbionts. The ultrastructure, cell physiology, development, biochemistry, genetics, and
highlight some of our successes and challenges. We molecular biology of Tetrahymena havebeen extensively investigated and display a degree
of structural and functionalcomplexity comparable to that of human and other metazoan
phenotyped 9,600 first generation mice using broad- cells. Recentgenome sequencing projects have confirmed that these extensive
based, high-throughput screens. Of 2,218 outliers (2 andcomplex genomes conserve a rich set of ancestral eukaryotic functions.
Tetrahymena has allowed major discoveries in biology such as catalytic RNA and
SD), 293 were selected heritability testing. 127 were rybozymes (Nobel prize), variant nuclear genetic codes, telomeres and telomerase (Nobel
prize), histone acetyl transferase as a transcription factor/co-activator, and recently
heritable. 52 of the most interesting ones were mapped to discovered epigenetic phenomena acting at DNA (programmed somatic DNA
chromosome location. So far, 26 point mutations are rearrangement), RNA (e.g. RNA interference), and protein levels. Unique among
unicellular eukaryotes, ciliates separate germinal and somatic lines, in the form of nuclei.
identified and 24 mutants are listed in the International Somatic development involves programmed rearrangements of the entire germline genome
Mouse Strain Resource. Young adult mice were at each sexual generation and provides an excellent experimental model to study somatic
DNA rearrangements similar to those that generate antibody diversity and malignant states
screened for heart (15 heritable, 6 mapped, 2 cloned), in vertebrates. An impressive array of novel molecular genetic technologies place
blood (39 heritable, 13 mapped, 3 cloned), bone density Tetrahymena at the forefront of experimental, in vivo functional genomics research. These
tools include but are not limited to: facile maintenance of lethal mutations and essential
(17 heritable, 5 mapped, 2 cloned), neurobehavior/ gene knockouts in the silent germline of heterokaryons; high frequency DNA transformation
appearance (44 heritable, 23 mapped, 17 cloned), kidney with high-copy replicative vectors or by precise homologous recombination; easily
manipulated inducible promoters allowing effective regulation of gene expression; gene
(6 heritable, 2 mapped, 2 cloned), and other dysfunctions and protein tagging for protein localization and protein/protein interaction studies; use of
double stranded RNA for gene regulation; ribosomal antisense repression; and cloning by
(5 heritable, 3 mapped, 0 cloned). 46 heritable lines have complementation. The richness of its genome makes this a useful model for addressing
been distributed to 44 labs world-wide. CMHD’s cost- important questions including those with applications related to human health that cannot
be investigated in other unicellular eukaryotic microbial systems. I will present an overview
recovery phenotyping (www.cmhd.ca) has been used by of features of Tetrahymena making it a powerful animal model organism, focusing on
170 investigators across Canada and USA. epigenetic mechanisms involving RNAi and heterochromatin in irreversible gene silencing.

7. Dr. Joseph Culotti Dr. Michelle Bendeck
Professor, Department of Professor,Department of
Molecular and Medical Laboratory Medicine and
Genetics, University of Pathobiology,University of
Toronto, Senior Investigator Toronto
Samuel Lunenfeld Research
Institute, Mount Sinai
Hospital, Toronto, Canada
Molecular mechanisms underlying cell and axon The role of the extracellular matrix in atherosclerotic
migrations in C. elegans inflammation, fibrosis and calcification
A novel TGF-beta and a G-protein coupled receptor are Interaction between cells and the extracellular
involved in UNC-6/netrin mediated axon guidance and matrix provide structural support in the blood
cell migration in C. elegans.
Jasmine Plummer and Joe Culotti.
vessel, and allow the opportunity for signaling and
The netrin axon guidance and cell migration cue was first discovered as a mechanotransduction. Collagens are abundant in
predicted product of the unc-6 gene in C. elegans, where it was shown to
mediate both attractive and repulsive responses depending on the repertoire
the atherosclerotic plaque, and these molecules
of UNC-5/RCM and UNC-40/DCC receptors expressed by these cells. By play both protective and harmful roles in
ectopically expressing UNC-5 in specific sensory neurons that already
expressed UNC-40, we made their axons switch from an attractive response to atherogenesis. My lab is studying the discoidin
a repulsive response to UNC-6. We showed the new ‘switched’ UNC-6-
dependent guidance response was sensitized to the dose of unc-6(+) and
domain receptor 1 (DDR1), a collagen-binding
used the ‘switched’ strain to carry out a genetic screen for suppressors of the receptor tyrosine kinase. We have recently
‘switched’ phenotype to identify additional genes that act in the UNC-6 – UNC-
5 signaling pathway. In this screen we recovered weak alleles of unc-6 and
described a critical role for DDR1 in atherosclerotic
unc-40, showing the screen worked as hoped. We also discovered unc-129 - plaque development, regulating inflammation,
mutations of cause motor axon guidance defects resulting in uncoordinated
locomotion. We found that unc-129 encodes a novel TGF-beta that acts fibrosis, and calcification in a mouse model of the
through a non-classical signaling mechanism to regulate sensitivity of growth
cones to UNC-6. We also recently discovered a mutation that suppresses the
disease. I will discuss our ongoing work to elucidate
‘switched’ phenotype, which on its own does not normally cause motor axon the cellular, molecular and signaling mechanisms.
guidance defects suggesting it has a redundant function with another guidance
gene. This mutation identifies the seu-2 gene which we have found encodes a
Taken together , our studies suggest that inhibition
novel G-protein coupled receptor (GPCR) involved in both attractive and of DDR1 may be an important therapeutic target to
repulsive responses to UNC-6. Finally, we have found that this GPCR
functions in neurons whose axon guidance is affected by seu-2 mutations. limit inflammation, calcification and plaque growth,
Since GPCRs are targets of most pharmaceuticals of clinical relevance, we
hope that understanding how this GPCR functions will lead to improved
and to promote stability.
pharmacological interventions for human disorders that are sensitive to
increased or decreased netrin-mediated signaling.

8. Dr. Szczepan Baran Dr. Levon Khachigian
President and Chief Director, UNSW Centre for
Operating Officer, Veterinary Vascular Research, University
Bioscience Institute in of New South Wales, Sydney,
Harleysville, Pennsylvania Australia
Rat laparoscopic biopsies lead to decreased Immediate-early genes as master regulators in a
postoperative pain wide range of vascular disorders
The refinement of current surgical techniques represents
Cardiovascular disease and cancer remain the most prevalent
a key opportunity to improve the welfare of laboratory
causes of morbidity and mortality. The pathogenesis of these and a
rodents, while meeting legal and ethical obligations. myriad of related diseases is underpinned by molecular and cellular
Minimally invasive surgery such as laparoscopy is changes in our blood vessels. Professor Khachigian’s research is
considered the gold standard for many human uncovering key networks of transcriptional control and inducible
abdominal procedures. Laparoscopy results in gene-regulatory circuits that lead to vascular disease. The group is
decreased pain, decreased tissue trauma and more also developing new experimental drugs that have the potential to
treat a diverse range of health problems, from cancer and
rapid post surgical recovery. Compared to laparotomy,
inflammation through to eye and heart disease. research program
laparoscopy preserves immune function when has two major objectives: 1. To better understand how harmful
equivalent procedures are performed. Many of these genes are controlled in vascular cells. This arm investigates
benefits have been demonstrated in rodents with the signaling and transcriptional mechanisms of pro-inflammatory
exception of pain management. A pilot study was cytokine-dependent gene expression, post-translational mechanisms
conducted using three groups; rats that had undergone that modify protein behavior, proteinase control, the isolation and
characterization of new genes induced or repressed by vascular cell
laparoscopic liver biopsy via laparoscopy, rats that had
injury, and the molecular control of vascular cell migration and
undergone liver biopsy via laparotomy, and rats exposed proliferation. The group has considerable expertise in animal models
to inhalant anesthesia alone. Preliminary data, which of neointima formation, angiogenesis, tumor growth, myocardial
included quantitative behavior analysis of assessing ischemia, and inflammation. 2. To develop new vascular therapeutic
post-operative pain, demonstrated that laparoscopic agents. The lab is harnessing the outcomes of its fundamental
procedures lead to less post surgical pain than research by pioneering the development of novel “anti-gene-” and
“gene-therapeutic” strategies targeting key regulatory genes in a
laparotomy. Additional studies are required, but this
myriad of vascular disorders. This involves strategic collaborations
initial data suggest that laparoscopy in rodents might with a range of clinical specialists, academics and drug development
represent a significant surgical refinement for the consultants.
reduction of post-operative pain.

9. Dr. Adam Karpf Dr. Milton Charlton
Associate Professor, Professor,Department of
Roswell Park Cancer Physiology,University of
Institute, Department Toronto
of Pharmacology and
Therapeutics
Buffalo, NY
DNA methylation in murine prostate cancer Squid, Frog, Crayfish, and Drosophila models in
DNA methylation in mammals is a covalent modification of Neuroscience
cytosine residues residing within CpG dinucleotides, and is Basic neuronal mechanisms are highly conserved and all discoveries
catalyzed by DNMT enzymes post DNA replication. DNA of these mechanisms made in Invertebrates have been confirmed later
methylation plays a critical role in mammalian development, in mammals. The large presynaptic terminal of the squid giant
genomic imprinting, transcriptional regulation, X-chromosome synapse allows voltage clamping of calcium currents and injection of
inactivation, and genomic stability. Notably, abnormalities in chemicals and proteins into the transmitter release sites. Basic
DNA methylation are ubiquitous in human cancer. These concepts of calcium signaling were developed with this preparation
changes include both DNA hypermethylation and and these ideas were used in stroke research. The quantal nature of
hypomethylation, which occur at distinct regions of the genome. transmitter release was discovered in the frog neuromuscular junction
While substantial correlative data exist linking DNA methylation (NMJ). The regular array of active zones where exocytosis occurs
changes to human cancer, in vivo model systems will be was exploited to examine the exclusive localization of calcium
required to elucidate the functional role of these changes in channels. Invertebrate NMJs have been the source of several
tumor development and progression. Our laboratory is seminal discoveries in Neuroscience such as the mechanism of
conducting studies that utilize the TRansgenic Adenocarcinoma presynaptic inhibition. The crayfish NMJ has a small number of
of Mouse Prostate (TRAMP) model to define the nature and identified presynaptic axons of large enough diameter to permit
contribution of DNA methylation changes to prostate cancer. We intracellular recording and injection. Moreover, there is a huge degree
have observed that DNA methylation abnormalities occur in a of presynaptic differentiation; synapses of different motorneurons differ
tumor-stage specific manner, and correlate with gene expression wildly in presynaptic release properties. Therefore, one can ask how
changes. Furthermore, we have shown that reduced expression synapses become different as a natural growth process rather than
of the Dnmt1 enzyme in TRAMP significantly alters tumor during pesky learning paradigms. The Drosophila NMJ also has few
development. Most prominent among the changes observed is a motor neurons innervating each muscle fibre but they are much thinner
striking reduction in tumor metastases. In summary, murine than in crayfish. However, Drosophila has the advantage of a known
models have proven useful for evaluating the functional genome and the availability of many mutants. Several mutations the
contribution of DNA methylation to prostate cancer. model human diseases are available. For instance there is a
Drosophila model of Niemann-Pick disease in which there is abnormal
membrane cholesterol distribution. We have studied the importance of
membrane and synaptic vesicle cholesterol by exploiting a Drosophila
dynamin mutant which allows access to the vesicle lumen.

10. Dr. Zhong-Ping Feng Dr. David Rollo
Associate Professor, Professor, Department of
Department of Biology, McMaster University
Physiology, University of
Toronto
Lymnaea stagnalis, a multitalented model in
Aging and Development of Successful Dietary
integrative neurophysiology
The freshwater pond snail, Lymnaea stagnalis (L. stagnalis) has
Interventions: Lessons from Transgenic
served as a model for a wide spectrum of fundamental studies in Growth Hormone Mice That Express a
molecular, cellular, and behavioral neurobiology. One of the Progeroid Syndrome of Accelerated Aging.
major advantages of L. stagnalis is its simple central nervous
system (CNS). The snail central neurons are large and many of Diverse pathologies including cardiovascular disease, stroke,
them are individually identifiable, thus allowing diabetes, obesity, neurodegenerative conditions, cancer and
electrophysiological dissection of neuronal networks in vivo. inflammation are associated with elevated free radical
Studies using L. stagnalis as a model have made significant processes. Most of these are age-related so slowing aging
contributions in our understanding of the biophysical properties could ameliorate all of these conditions simultaneously.
of neurons, synaptic transmission, and neural networks involved Dietary supplements composed of one or a few ingredients
in feeding, respiration, defensive withdrawal, locomotion, gravity have had little success. We formulated a complex dietary
orientation, reproduction, and learning and memory. Individual supplement targeting five key processes of aging and tested
neurons that are identified as parts of defined behavioural it on normal mice and transgenic mice expressing accelerated
circuits in adult animal can be isolated and maintained in cell aging. The supplement prevented age-related cognitive
culture, where synaptic connections reliably re-establish. This declines, forestalled bradykinesis (declining physical activity),
property of the snail serves as an excellent tool to study the upregulated neurotransmitters, ameliorated radiation-induced
specificity of synapse remodelling between adult neurons. We DNA damage and apoptosis, reversed declines in
have taken advantages of the CNS of L. stagnalis, in mitochondrial activity, and increased longevity. Remarkably,
combination with acute targeted-gene silencing approaches, to the supplement reduced mitochondrial protein carbonyls per
identify novel cellular and molecular mechanisms in neuronal unit complex III activity by ~ 50%. Reduction of free radical
regeneration, synapse formation, memory formation, and hypoxic generation by mitochondria (a cleaner burn) is considered the
stress. Our recent large-scale transcriptome sequencing and critical mechanism extending longevities in dietary restricted
proteomics analyses of the L. stagnalis CNS have identified a animals and birds and is considered the “silver bullet” for
number of molecules that are orthologues to the genes related to aging interventions. Results provide proof of principle that
neurological disorders. In light of these new findings, the snail cocktails of dietary supplements may indeed extend youthful
model can be further used in functional genetics studies related function into older ages.
to neurodegenerative and neurodevelopmental diseases.

11. Dr. Jack Uetrecht Dr. Thomas Koch
Professor of Pharmacy and Adjunct Professor, Department
Medicine, CRC Chair in of Biomedical Sciences,
Ontario Veterinary College, U.
Adverse Drug Reactions,
of Guelph, Research
Leslie Dan Faculty of Associate Orthopaedic
Pharmacy, University of Research Laboratory, Aarhus
Toronto University Hospital, Denmark
Animal models to understand and ultimately Equine umbilical cord blood stem cell and tissue
prevent idiosyncratic drug reactions engineering based therapies using the horse as a
Idiosyncratic drug reactions (IDRs) are a major source of patient morbidity and pre-clinical animal model of orthopedic problems
mortality. They also significantly increase the risk of drug development because Stem cells and tissue engineering have received considerable attention due to
they are not discovered until very late in development and often after a drug has their potential therapeutic use in the past few decades although none of the
been marketed. There is little known with certainty about their mechanisms and commercially approved products as of late 2002 had made a profit despite a total
without such understanding we are unlikely to make progress in predicting and industry investment in research and development exceeding US dollar 4.5 billion.
preventing IDRs. Their unpredictability make prospective human mechanistic The causes of the inadequate return of these investments are undoubtly
studies impossible, and although animals can also have IDRs they are also multifacorial, but there is an emerging recognition in the biomedical field of the
idiosyncratic in animals. Therefore, there are almost no valid animal models of need for intermediate animal models, which can bridge the proof-of-principle
IDRs. We have developed one animal model in which nevirapine causes a skin studies in small laboratory animals and human clinical trials. The animal models
rash in rats that is very similar to the rash that it causes in humans. This rash is of experimental induced arthroses currently used to assess biological safety and
caused by a metabolite of nevirapine and it is immune-mediated. In particular, efficacy appear fundamentally flawed. The reason being that the joint and
substitution of deuterium for hydrogen on the molecule at the site of reactive cartilage environment of a spontaneously occurring lesion of possible long-lasting
metabolite formation decreases the incidence of rash and sensitivity to duration may very well be significantly different than the environment of limited
nevirapine can be transferred to naïve animals with spleen cells. Depletion of acute injuries induced in a otherwise healthy joint. If this notion is accepted, then
CD4+ T cells is protective but depletion of CD8+ T cells appears to make the the cellular tissue response of both implanted and native cells and tissues may
rash worse. This model is very helpful in studies of how small molecules can also behave significantly differently. A number of domestic animals could serve
lead to an immune response. However, different drugs cause IDRs with different as models of spontaneous joint lesions. Specifically, comparative studies have
characteristics and this presumably reflects mechanistic differences. Therefore, shown that the articular cartilage thickness of horses most closely resembles that
we need several animal models to determine to what degree the mechanisms of of human articular cartilage. Both induced arthroses and spontaneous cartilage
different IDRs differ. We discovered the nevirapine model by accident, but if defects can be studied in the Horse. Spontaneous joint problems are a common
most IDRs are caused by chemically reactive metabolites and immune- problem in horses and the familiarity of horses to being handled makes them an
mediated it should be possible to develop new animal models by increasing the ideal species to evaluate selected rehabilitation programs. The significance of
production of reactive metabolites, stimulating the immune system and inhibiting weight-bearing/loading of joint immediately post-operatively is another important
immune tolerance. However, despite several years of work, these strategies parameter that can be assessed using the horse as an animal model. This is of
have not been successful. Furthermore, even though we know that the particular interest in human medicine where so-called fast-track surgery
nevirapine-induced skin rash is immune-mediated, factors that would be programs are being increasingly implemented to decrease co-morbidities related
expected to increase its incidence/severity have not had the expected effects. to bed rest and inactivity post-operatively. The recent isolation of multipotent
Therefore, our inability to develop animal models by trying to manipulate the mesenchymal stromal cells (MSCs) from equine umbilical cord blood makes for a
immune response to not mean that other IDRs are not immune-mediated. It very interesting research opportunity evaluating these cells utility in cartilage
does indicate that we have a limited understanding of the immune system. repair in the horse.

12. Dr. John L. Wallace Dr. Jeffrey Henderson
Director, Farncombe Family Associate Professor,
Leslie Dan Faculty of Pharmacy,
Digestive Health Research University of Toronto
Institute, McMaster Director, Murine Imaging and
University Histology (MIH) Facility
Studying Human GI Inflammation and Ulceration Development of Interactive Surgical and Multimodal
Using Rodent Models Atlases of the mouse CNS:Toward Integrative
Neuroanatomic Measures
Inflammation plays in important role in the pathogenesis
of several common diseases of the gastrointestinal (GI) Over the past quarter century genetically modified mice have emerged as
major experimental models to probe fundamental aspects of the
tract, including inflammatory bowel disease, celiac mammalian CNS; both during development and following injury. The
disease, peptic ulcer and the gastroenteropathies morphologic effects resulting from a given gene targeting or CNS injury
associated with the use of nonsteroidal anti- event frequently manifest itself at multiple neuroanatomic loci. Accurate
inflammatory drugs (NSAIDs). Over the past few integrated interpretation and/or quantitative assessment of such features
are often difficult or impossible to determine using standard histologic
decades, a great deal has been learned about the measures. In order to enhance investigators ability to more robustly analyze
pathogenesis of these and other GI disorders through the effects of these and other interventions, we have developed two open
the use of animal models. For example, several rodent source tools toexamine the comparative neuroanatomy of the mouse CNS.
In the first, we examined population-based variability of the CNS in
models of colitis have been developed which have been
129S1/SvImJ,C57Bl/6J inbred and CD1 outbred strains of mice.
exploited for testing of novel therapies, but also for Determining the limits of such natural variability represents a requisite
investigating potential mechanisms of tissue injury and precondition to provide confidence limits to any morphologic changes seen
repair. Similar, models of NSAID-induced GI injury have following intervention. In the second, we analyzed the brain and skull of
numerous murine strains to develop a new more robust and accurate
been widely employed to better understand these stereotactic coordinate system providing improved stereotactic accuracy.
conditions, and to develop safer anti-inflammatory We have utilized these tools to develop the first detailed three dimensional
drugs. These models have also been used to study understanding of how EphB-type receptors regulate guidance decisions
endogenous mediators of resolution of inflammation required for formation of the anterior commissure (AC) in the murine
forebrain. Using this system we demonstrate for the first time that loss of
(i.e., anti-inflammatory signals), and of healing. EphA4 results in significant displacement of the AC pars anterior into
regions which developmentally express isoforms of EphA4 repulsive cues.
We also demonstrate that EphB2 and EphA4 regulate distinct aspects of
axon guidance within the pars posterior of the AC, and that these receptors
act synergistically to prevent axons within the AC par anterior from mis-
projecting caudally.