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Catherine Tsilfidis, Ph. D.
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Senior Scientist, Vision, Ottawa Hospital Research Institute
Associate Professor - Departments of Ophthalmology and Cellular and Molecular Medicine, University of Ottawa
Biographical Sketch
I obtained my Ph. D. from the University of Toronto, working in Richard Liversage's laboratory in the area of developmental biology. My project examined the effects of nerves on Xenopus laevis forelimb regeneration. Post-doctoral studies were carried out at the Children's Hospital of Eastern Ontario in Robert Korneluk's laboratory. Our team was one of several which discovered the gene which causes myotonic dystrophy, a form of muscular dystrophy. From 1993 to April, 2000 I was a researcher at the Eye Institute in Toronto (with appointments to the Departments of Ophthalmology and Zoology at the University of Toronto). Projects in my lab involved a genetic analysis of autosomal dominant congenital cataracts and the molecular aspects of forelimb regeneration in the newt, Notophthalmus viridescens. I have been at the OHRI (at the University of Ottawa Eye Institute) since April, 2000.
Research Interests
- Molecular aspects of forelimb and lens regeneration in the newt, Notophthalmus viridescens
- Dedifferentiation as a source of stem cells in the regeneration process
- Gene therapy in retinal degeneration using XIAP, a potent inhibitor of apoptosis
- Stem cell applications to retinal damage or disease
Major Research Activities
There are two major research focuses in the lab.
Research Focus I: Regeneration in the newt, Notophthalmus viridescens.
Amphibians such as the newt, Notophthalmus viridescens, have a unique ability to regenerate arms legs, spinal cord, eye structures and many vital organs. Through a process called epimorphic regeneration, structures lost to injury or amputation are replaced, such that the regenerated structure is indistinguishable from the original. An understanding of the basic mechanisms involved in these processes will not only advance our fundamental knowledge of the biology of regeneration, but will also have considerable clinical implications for humans. The most critical stage in the regeneration response, and the reason why some amphibians possess the ability to regenerate, is their ability to induce the tissues at the site of injury to revert to an embryonic-like state - a process called dedifferentiation. An understanding of the molecular mechanisms involved in dedifferentiation is essential in order to enhance the regenerative ability in non-regenerating animals.
One of the major research aims of my laboratory is to identify factors controlling the onset of dedifferentiation so that we may use these factors to improve regenerative potential in man. We have used representational difference analysis (RDA) to isolate genes which may play key roles during dedifferentiation. We are currently in the process of characterizing some of these genes.
Recent studies have shown that mammalian cells have the capacity to dedifferentiate if given the appropriate triggers. Newt regeneration extracts have been used to induce dedifferentiation of fully differentiated mammalian muscle cells. We are examining the mammalian dedifferentiation response following treatment with newt extract. Our research examines the extent of pluripotentiality of these cells, and their ability to redifferentiate. We are also studying the gene expression profiles of these cells following treatment with newt extracts.
Research Focus II: Gene and stem cell therapy in animal models of retinal degeneration
Inherited retinal degenerations lead to a progressive loss of vision. Most often, they are characterized by a gradual loss of the photoreceptors in the retina. Cell death occurs through the process of apoptosis. We believe that regardless of the genetic mutation which a cell possesses, if we can target and prevent the ultimate death of the cell, we will be able to retain function in the photoreceptors and prevent vision loss. We are using inhibitors of apoptosis (IAPs) to try to prevent the retinal degeneration which is associated with diseases such as retinitis pigmentosa, retinal ischemia, or glaucoma. XIAP (the X-linked inhibitor of apoptosis protein) prevents apoptosis by blocking the action of caspases, which are enzymes that are involved in the cell death pathway. Adeno-associated virus encoding XIAP is injected into the sub-retinal space in the eye, and infects photoreceptor cells with high efficiency. We have used this approach to show that XIAP protects photoreceptors in animal models of chemotoxic damage, retinal ischemia and retinitis pigmentosa. These results hold tremendous promise for the treatment of human retinal diseases.
We are also interested in studying the ability of adult stem cells to repair damage caused by retinal ischemia or photoreceptor degeneration. We will deliver stem cells into the damaged eye and monitor cell survival, migration and integration. We will determine whether the introduced stem cells migrate to the correct layers of the retina, make the correct connections and acquire the characteristics of neighbouring cells.
Honours and Awards
2003-2008 Don and Joy Maclaren Chair for Vision Research
Current Funding Sources
07/2005 to 06/2008 – Muscular Dystrophy Association (MDA-USA)
04/2006 – 03/2009 – Canadian Institutes of Health Research (CIHR)
04/2005 – 03/2008 – Natural Sciences and Engineering Research Council of Canada (NSERC)
Publications:
Renwick, J., M. A. Narang, S.G. Coupland, J.Y. Xuan, A.N. Baker, J. Brousseau, D. Petrin, R. Munger, B. Leonard, W.W. Hauswirth and C. Tsilfidis (2006). XIAP-mediated neuroprotection in retinal ischemia. Gene Therapy 13(4):339-47.
Beug, S., S. G. Vascotto and C. Tsilfidis (2006). The newt orthologue of Growth arrest-specific 6 (NvGas6) is implicated in stress response during newt forelimb regeneration. Dev. Dynamics, 235(3):711-22
S.G. Vascotto, S. Beug, R.A. Liversage, C. Tsilfidis (2006).Expression profiles of newt elastase1 (NvElastaseI) and secretory leukocyte protease inhibitor (NvSLPI) during limb regeneration suggest a role in epithelial remodelling and delamination. Dev. Genes and Evol, Mar 1; [Epub ahead of print]
Vascotto, S., S. Beug, R.A. Liversage, and C. Tsilfidis (2005). Identification of cDNAs Enriched for the Dedifferentiation Stage in Adult Newt Forelimb Regeneration. Dev Dyn. 2005 Mar 23 [Epub ahead of print].
Cameron, C., S. Beug and C. Tsilfidis (2004). Captive breeding of Notophthalmus viridescens through hormonal manipulation. Herpetol. Rev. 35(3): 257-259.
Vlaskalin, T., C. Wong and C. Tsilfidis (2004). Growth and apoptosis during larval forelimb development and adult forelimb regeneration in the newt, Notophthalmus viridescens. Dev. Genes and Evol. 214(9): 423-431.
Petrin, D., A. Baker, S.G. Coupland, P. Liston, M. Narang, K. Damji, B. Leonard, V.A. Chiodo, A. Timmers, W. Hauswirth, R.G. Korneluk, C. Tsilfidis (2003). Structural And functional protection of photoreceptors from MNU-induced retinal degeneration by the X-Linked Inhibitor of Apoptosis. Invest. Ophthal. Vis. Sci.44(6): 2757-2763.
Petrin, D., A. Baker, J. Brousseau, S. Coupland, P. Liston, W.W. Hauswirth, , R.G. Korneluk, and C. Tsilfidis (2003). XIAP protects photoreceptors from N-methyl-N-nitrosourea-induced retinal degeneration. In Retinal Degenerations: Mechanisms and Experimental Therapy. M.M. LaVail, J.G. Hollyfield, and R.E. Anderson, eds., Kluwer Academic/Plenum Publishers, New York. Advances in Exp. Med. Biol. 533: 385-393.
Barr, C.L., A. V. Levin, R. Kovacs, W. Muller, M. Barsoum- Homsy, D. Zachary, R.A. Clark, C. Tsilfidis (2003). Linkage study between congenital cataracts and five crystallin loci. Am. J. Med. Genet. 121A: 15-19.
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