FFB Funded Research Grants Approved 2007 - 2008
The following is a list of new research grants and awards approved for funding, beginning July 1, 2007. The fiscal period for research grants begin July 1st each year and ends June 30th the following year.
Operating Grants
Torben Bech-Hansen
University of Calgary
Genetic and Molecular studies of CSNB in man and mouse
Granted: $270,000 over 3 years (plus $12,000 in first year for equipment), July 2007 – June 2010
Dr. Torben at the University of Calgary will focus on finding the underlying genetic causes of inherited retinal diseases, and understanding how these genetic defects disrupt the function of the retina and cause impaired vision and blindness. In particular, he will study a group of disorders called Congenital Stationary Night Blindness (CSNB). Patients with CSNB present with several of the following features: impaired visual acuity, poor night vision or night blindness, myopia (short sightedness), nystagmus (involuntary eye movement) and strabismus (misaligned eye). We have identified the genes responsible for the two common forms of CSNB (CSNB1 and CSNB2). One of these genes, CACNA1F, codes for a specific calcium channel protein that is present in photoreceptors, while the second gene produces a protein called nyctalopin, which is attached to the outside of retinal nerve cells but whose function is not known.
In ongoing studies using DNA samples from CSNB patients from various eye centres across Canada, USA and Europe, we are evaluating what other genes may cause CSNB. In another study, we generated a model of the CSNB2 condition by putting a mutation into the CACNA1F gene of the mouse. Studying the retina of this mutant mouse revealed structural and functional features suggesting that the retinal defect in patients with CSNB2 may be the failure to form proper synaptic junctions between photoreceptors and their fellow retinal nerve cells, in this way preventing the transfer of the visual signal from the photoreceptors to the visual centre of the brain. We are investigating this possibility by using novel methods of inspecting the human retina. Furthermore, we are using our mutant CACNA1F mouse to identify genes that influence the clinical severity seen among patients with CSNB2. The proteins of such modifier genes, we expect, will represent important molecular targets for treatment of CSNB.
In summary, our studies provide the basis for definitive molecular diagnosis of CSNB, the opportunity to understand the biological causes of CSNB, and for defining the clinical picture of various forms of CSNB and identifying suitable molecular targets that could led us to treatment strategies for CSNB.
Gilbert Bernier
Maisonneuve-Rosemont Hospital
Stem Cell Transplantation for the Treatment of Retinal Degenerative Disease
Granted: $151,000 over 2 years, July 2007 – June 2009
Degenerative diseases of the retina, such as RP and AMD, destroy vision by causing the death of rod and cone photoreceptor cells. There is currently no cure for most retinal degenerative diseases. Dr. Bernier at Maisonneuve-Rosemont Hospital is conducting a study that tests whether transplanting stem cells into the retinas of mice with retinal degeneration can save vision. Researchers will monitor the survival and formation of these transplanted cells in mice. This is important because stem cells can provide an unlimited source of cells for transplantation. If successful, this work will be expanded to larger animal models of retinal degeneration, which are closer to human conditions.
Robert L. Chow
University of Victoria
Mouse models of human VSX1-associated retinal and corneal disease
Granted: $225,000 over 3 years, July 2007 – June 2010
Dr. Robert Chow at the University of Victoria is investigating whether mutations of the gene, VSX1, which are associated with human retinal circuitry dysfunction, macular degeneration and corneal dystrophies, are causing these diseases. In the research community, it is currently unresolved whether these VSX1 mutations cause eye disease because researchers don’t know what role VSX1 plays in cone photoreceptor function, macular degeneration or corneal well-being. As part of his research, Dr. Chow’s lab will study mice with mutations in their VSX1 gene which are identical to those identified in humans. Demonstrating what role these VSX1 mutations play in eye disease aids in understanding these diseases. These findings can help in the clinical diagnosis of these diseases and provide essential information for the development of treatments and cures.
Jane McGlade - Arthur and Sonia Labatt Endowment
Hospital for Sick Children
Regulation of CRB in PRC morphogenesis and survi
Granted: $270,000 over 3 years, July 2007 – June 2010
Dr. Jane McGlade at the Hospital for Sick Children in Toronto is studying how CRB1 gene mutations cause retinal degeneration, by examining how these mutations affect the structure and survival of photoreceptor cells (rods and cones in the eye that capture light). This is important because CRB1 genes are responsible for 4% of autosomal recessive RP (RP12) and 10-15% of cases of Leber congenital amaurosis. While researchers don’t fully understand the role that CRB1 plays in these diseases, previous studies have shown that the CRB1 gene maintains the proper structure of photoreceptor cells and protects them from stresses that can cause cell death. To function properly the CRB1 protein forms connections with other proteins. Dr. McGlade will study how these proteins interact with CRB1 and then determine the role of these proteins in mouse retina development and degeneration. The goal of this research is to gain clear understanding of how CRB1 mutations lead to retinal degeneration. This information will point to potential therapeutic approaches aimed at restoring CRB1 function to prevent retinal degeneration.
Ulrich Tepass
University of Toronto
Drosophila models for retinal degeneration
Granted: $270,000 over 3 years, July 2007 – June 2010
Photoreceptors (rods and cones that capture light) are important for healthy vision. But when there are mutations in the genes responsible for keeping photoreceptors healthy, it causes retinal degenerations and blindness. Dr. Ulrich Tepass at the University of Toronto is studying the formation and maintenance of retinal photoreceptor cells in fruit flies. The same molecules contribute to the formation of the retina in fruit flies and humans. This study is important because it will generate valuable information about the molecules controlling the design of photoreceptors and this could eventually open up new avenues for therapeutic strategies for the prevention or treatment of retinal degenerations (RP).
Postdoctoral Fellowships
Mélanie Reneé Lalonde - FFB/BMO Financial Postdoctoral Fellowship in Genetic Research
Supervisor: Alan J. Mears, Ph.D.
Ottawa Hospital Research Institute
Identifying the genetic determinants of photoreceptor development and function
Granted: $35,000 for 2 years, July 2007 – June 2008
The focus of Dr. Melanie Lalonde’s research is to understand the specific genes involved in the differentiation and function of photoreceptors (rods and cones), light sensing cells in the retina, in diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD).
A number of possible genes that may play a role in the development and/or function of photoreceptors were identified using Affymetrix technology, a technique that analyzes the expression of many thousands of genes simultaneously. Interesting candidate genes which may be important for cone development include ClCa3, Otop3, Prickle2, and Sall3.
By identifying photoreceptor-specific genes involved in human rod and cone dystrophies therapies for RP or AMD, such as stem cell translpantaion to treat or replace lost photorecpetors, can be developed.
Dr. Lalonde has recently accepted the position of Clinical Research Program Manager at the University of Ottawa Eye Institute. Her postdoctoral fellowhip training had a tremendous impact on her current position. She has now a strong background in both the clinic and basic approaches for studying vision, related diseases, and future therapeutic treatments that may be employed to treat retinal disorders.
Frank M. Dyka
Supervisor: Robert S. Molday, PhD.
University of British Columbia
The role of Retinoschisin (RS1) in Juvenile Macular Degeneration
Granted: $70,000 over 2 years, July 2007 – June 2009
Dr. Dyka at the University of British Columbia is investigating the role of the protein retinoschisin in X-linked retinoschisis, an inherited form of macular degeneration that affects males at an early age. This degenerative disease is characterized by a splitting of the retina and a marked loss in central vision. The goal of this research project is to determine how retinoschisin maintains the unique cellular organization of the retina and how disease-causing mutations alter this function. During the past year Dr. Dyka was successful in producing and purifying significant amounts of the retinoschisin protein. This has enabled him to study the structural and functional properties of retinoschisin and identify interacting proteins. Further analysis of retinoschisin and its interacting proteins will provide new insights in the molecular and cellular mechanisms underlying the X-linked retinoschisis. Knowledge gained through this study will contribute to the development of future treatments for this disease.
Karine Zaniolo
Supervisor: Sylvain Chemtob, PhD.
Centre Hospitalier Universitaire Mere-Enfant
Krebs cycle intermediates: Novel mediators of retinal angliogenesis and implications in ischemic retinopathy
Granted: $105,000 over 3 years, July 2007 – June 2010
Neovascularization (formation of new blood vessels) is a major cause of retinal disease and loss of vision in people with diabetes and the wet form of age-related macular degeneration (AMD). It also plays a role in retinopathy of prematurity (ROP), which causes vision loss in prematurely born babies. Dr. Zaniolo at the Research Centre of Sainte-Justine Hospital will determine whether a novel metabolic signal, called succinate, causes neovascularization in a model of ROP. If the study finds succinate stimulates neovascularization in the eye, it might be a target for new therapies to combat ROP and other sight-threatening diseases.
The main current medical therapy to stop the growth of new blood vessels in the retina is a treatment that blocks the action of VEGF, a growth factor that stimulates blood vessel development in those with wet AMD. Because anti-VEGF therapies are expensive and require repeated injections into the eye, it is important to continue the search for cheaper and less invasive ways to inhibit neovascularization.
Graduate Student Scholarships
Alexa Bramall
Supervisor: Roderick McInnes, PhD.
Hospital for Sick Children
Endothelin-2 and Inherited Photoreceptor Degeneration
Granted: $60,000 over 3 years, July 2007 – June 2010
Retinitis pigmentosa (RP) is the most common form of inherited blindness. It causes the progressive degeneration of photoreceptors (PRs), or the light-sensing cells of the retina. There are more than 130 genes which can cause inherited photoreceptor degeneration (IPD), but little is known about how the mutated PRs die. Alexa Bramall, a graduate student working at the Hospital for Sick Children, is conducting research to explain this degenerative process. By understanding the events proceeding PR cell death, researchers can begin to develop the treatments needed to prevent or slow down the disease.
In her research, Alexa is working with a gene that has been implicated in many types of inherited photoreceptor degeneration, environmental and genetic. She has shown that the absence of this gene in mice rescues close to 50% of the photoreceptors in the retina. If this protection of PRs can be replicated in humans, e.g. by inhibiting the gene product or using compounds that block downstream signaling pathways, then this research holds much promise for the development of future therapies to treat RP and possibly other retinal disorders.
Vasanth Ramamurthy
Supervisor: Michel Cayouette, PhD.
Institut de recherches cliniques de Montréal
Role of numb in photoreceptor development
Granted: $60,000 over 3 years, July 2007 – June 2010
Photoreceptors (PR) are light sensing cells in the retina that play a critical role in converting light into an electrical activity that can is interpreted as images by the brain. When photoreceptors degenerate, it leads to blindness and is characteristic of diseases such as Retinitis Pigementosa (RP). Degeneration of photoreceptors is caused by certain mutations in genes. It is important to understand the biological processes involved in the development of photoreceptors to tackle diseases like RP.
Vasanth Ramamurthy, a PhD student at the Institut de recherches cliniques de Montréal, recently discovered a protein that appears to be involved in the development of photoreceptors. He and his team plan to investigate, in detail, the role of this protein and its function in the photoreceptor. The study could lead to the discovery of new mutations which contribute to RP and other photoreceptor degenerative diseases.
Jean Peloquin
Supervisor: John McRory, PhD.
University of Calgary
Exploring the effects of multiple mutations found in Cav1.4 calcium channel associated with X-linked.
Granted: $20,000 over 1 year, July 2007 – Dec 2007
Mylene Pouliot
Supervisor: Réjean Couture, PhD.
Université de Montréal
Kinins involvement in vascular aspects of diabetic retinopathy in rats
Granted: $60,000 over 3 years, July 2007 – June 2010
Diabetes is the most common cause of blindness in the working-age adult population in North America. This vision loss results from damage to the retina because of blood supply failure. Circulatory failure in diabetes is due to the sustained high concentration of blood glucose and to inflammation. Inflammation results in the production of “kinins”, chemical signaling molecules that may change retinal blood flow by interacting with the receptor “B1R” on blood vessels. The main hypothesis to be tested by Mylène Pouliot (University of Montreal) is that the specific B1R-blocking drug will prevent diabetic retinopathy. Since the targeted receptor, B1R, is found only in damaged tissues, drugs directed against it would affect only those tissues that have been affected by diabetes. This study will also help researchers to understand better how blood flow is regulated in the eye. It might also lead to better therapies for any retinal disease in which inflammation-derived kinins and blood vessel problems are involved, such as uveitis and even AMD.