Scientific Centres

Biographical Sketch

Robert G. Korneluk obtained his Ph.D. in developmental biology from the University of Toronto in 1982. He trained from 1982 to 1985 as an MRC post-doctoral fellow in molecular genetics at the Hospital for Sick Children, Research Institute in Toronto. He is currently a Professor of Pediatrics at the University of Ottawa and is cross-appointed to the Department of Biochemistry, Microbiology and Immunology. He is a Canadian Institutes of Health Research (CIHR) Senior Scientist, Howard Hughes Medical Institute (HHMI) International Research Scholar and a Fellow of the Royal Society of Canada (FRSC).

Dr. Korneluk, along with Dr. Alex MacKenzie, are co-founders of the biotech company AEgera Therapeutics Inc. Significant intellectual property of the Company is based upon the discovery by Drs. Korneluk and MacKenzie of a family of genes encoding inhibitor of apoptosis proteins (IAPs). AEgera has a current market capitalization of $45 million and is a drug discovery company whose mission is to identify compounds that will modulate apoptosis and have utility in neurodegeneration and cancer.

Research Interests

The modulation of programmed cell death (apoptosis) for therapeutic benefit in disease including myotonic dystrophy, retinal eye disease, diabetes, neurodegeneration and cancer.

Research Activities

My research program involves four areas of investigation, all of which ultimately converge on basic and fundamental mechanisms of apoptosis, or programmed cell death. A healthy degree of apoptosis is required for normal tissue development and cellular homeostasis. In contrast, dysregulation of apoptosis is involved with the pathogenesis of many diseases, ranging from cancer to neurodegeneration.

Cancer
We have identified a novel family of genes encoding Inhibitors of Apoptosis (IAP) proteins. We propose that elevated expression of these IAPs represents a key survival factor in cancer progression. We are studying the specific signaling pathways impinging on IAP expression and function. We are also investigating protein-protein interactions between the IAPs and, in particular, their intrinsic negative regulators. The biochemical, molecular and cellular investigation of IAP mechanism of action will allow us to construct mouse models of cancer involving the potential co-operation of oncogenes with these apoptotic suppressors.

Retinal Eye Disease
We have initiated an IAP-based gene therapy approach in preclinical (animal) models of retinal degeneration for the evaluation of therapeutic benefit. We have targeted the X-linked IAP (XIAP), using viral expression vectors, to photoreceptor cells and retinal ganglion cells in order to assess the rescue potential of this IAP in eye disease. We are also creating transgenic mouse lines that over-express XIAP in photoreceptor cells. These animals will be crossed with mice carrying genetic forms of retinal degeneration to evaluate the protective potential of XIAP. In addition, we will test the resistance of XIAP transgenic mice to chemical or light induced degeneration. We propose that many, if not all, forms of retinal degeneration involve apoptosis; preventing cell death with XIAP gene therapy may have utility in the treatment of a variety of eye diseases, regardless of the underlying genetic or physiological cause.

Type I Diabetes
Type I diabetes results from the autoimmune destruction of pancreatic beta cells. Since the death of beta cells is by apoptosis, we hypothesize that increasing resistance to cell death may have therapeutic utility. We have initiated XIAP gene therapy approaches to transduce isolated mouse pancreatic islets ex vivo. We will assess their resilience following transplantation into allogeneic, or syngeneic, diabetic recipients. Transgenic models have also been initiated in which human XIAP is over-expressed using beta cell specific promoters. Our initial results have demonstrated, surprisingly, that XIAP over-expression not only offers long-term protection of islet allografts but seems to prevent graft rejection altogether.

Myotonic Dystrophy (DM)
A long-term, ongoing research effort of my laboratory is to delineate the mechanism by which the DM mutation causes disease. DM is the result of the unstable expansion of a (CTG)n trinucleotide repeat in the 3’ untranslated (UTR) region of the DM protein kinase (DMPK) gene. Our working hypothesis is that the 3’UTR, in itself, confers a toxic gain-of-function upon mutant transcripts. We are modeling this disease in vitro using the differentiable mouse myoblast C2C12 cell line and human primary fibroblast and myoblast cells. We have evidence that the mutant CTG repeat, which is capable of forming double-stranded RNA (dsRNA) hairpin-loop structures, can activate the dsRNA-dependent kinase PKR. In turn, activated PKR is an important mediator of apoptosis. We are using in vitro (cell culture) and in vivo (transgenic) models to test the apoptosis hypothesis.

Selected Publications

Holcik, M., C.A. Lefebvre, K. Hicks and R.G. Korneluk (2002). Cloning and characterization of the rat homologues of the Inhibitor of Apoptosis protein 1, 2 and 3 genes. BMC Genomics 3:5.

McKinnon, S.J., D.M. Lehman, N.G. Tahzib, N.L. Ransom, H.A. Reitsamer, P. Liston, E. LaCasse, Q. Li, R.G. Korneluk, W.W. Hauswirth (2002). Baculoviral IAP repeat-containing 4 (BIRC4/XIAP) protects optic nerve axons in a rat glaucoma model. Molec. Therapy 5:780-787.

Perrelet, D, A. Ferri, P. Liston, P. Muzzin, R.G. Korneluk and A.C. Kato (2002). IAPs are essential for GDNF-mediated neuroprotective effects in injured motor neurons in vivo. Nat. Cell Biol. 2:175-179.

Quintero-Mora, M.L., F. Depardon, J. Waring, R.G. Korneluk, and B. Cisneros (2002). Expanded CTG repeats inhibit neuronal differentiation of the PC12 cell line. Biochem.Biophys.Res.Comm. 295:289-294.

Crocker, S.J., P. Liston, H. Anisman, C.J. Lee, P.D. Smith, N. Earl, C.S. Thompson, D. Park, R.G. Korneluk and G.S. Robertson (2003) Attenuation of MPTP-induced neurotoxicity and behavioural impairment in NSE-XIAP transgenic mice.  Neurobiology of Disease, 12:150-161.

Goping, I.S., M. Barry, P. Liston, T. Sawchuk, G. Constantinescu, K. Michalak, I. Shostak, D.L. Roberts, A.M. Hunter, R. Korneluk and R.C. Bleackley (2003). Granzyme B-induced apoptosis requires both direct caspace activation and relief of caspase inhibition. Immunity. 18:355-365.

Holcik, M., B.W. Gordon, and R.G. Korneluk (2003). The internal ribosome entry site-mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C1 and C2.  Mol. Cell. Biol. 23:280-288.

Hunter, A.M., D. Kottachchi, J. Lewis, C.S. Duckett, R.G. Korneluk, and P. Liston (2003).  A novel ubiquitin fusion system bypasses the mitochondria and generates biologically active Smac/DIABLO.  J. Biological Chem. 278:7494-7499.

Nevins, T.A., Z.M. Harder, R.G. Korneluk and M. Holcik (2003). Distinct regulation of  internal ribosome entry site-mediated translation following cellular stress is mediated by apoptotic fragments of eIF4G translation initiation factor family members eIF4GI and p97/DAP5/NAT1.  J. Biol. Chem. 278:3572-3579.

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, and C. Tsilfidis (2003). Structural and functional protection of photoreceptors from MNU-induced retinal degeneration by the X-linked inhibitor of apoptosis (XIAP).  Investigative Ophthalmology & Visual Science, 44:2757-2763.

Hu, Y., G. Cherton-Horvat, V. Dragowska, S. Baird, R.G. Korneluk, J.P. Durkin, and E.C. LaCasse (2003).  Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clinical Cancer Res 9:2826-2836.

Liston, P., W.G. Fong, and R.G. Korneluk (2003).  The inhibitors of apoptosis:  there is more to life than Bcl2.  Oncogene, 22:7568-8580.

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.  Adv. Exp. Med. Biol. 533:385-93.

Storbeck, C.J., S. Drmanic, K. Daniel, J.D. Waring, F.R. Jirik, D.J. Parry, N. Ahmed, L.A. Sabourin, J-E. Ikeda, and R.G. Korneluk (2004).  Inhibition of myogenesis in transgenic mice expressing the human DMPK 3’UTR.  Human Molecular Genetics, 13:589-600.

Perrelet, D., F.E. Perrin, P. Liston, R.G. Korneluk, A. MacKenzie, M. Ferrer-Alconland, and A.C. Kato (2004).  Motoneuron resistance to apoptotic cell death in vivo correlates with the ratio between XIAP and its inhibitor XAF1.  Journal of Neuroscience 24:3777-85.

Storbeck, C.J., K. Daniel, Y.H. Zhang, J. Lunde, A. Scime, A. Asakura, B. Jasmin, R.G. Korneluk and L. Sabourin (2004).  Ste20-like kinase SLK displays myofiber type specificity and is involved in C2C12 myoblast differentiation.  Muscle Nerve 28:553-64.

Ou, D., X. Wang, D.L. Metzger, R.F. James, P. Pozzilli, A. Plesner, R.G. Korneluk, C.B. Verchere, and A.J. Tingle (2005).  Synergistic inhibition of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human pancreatic beta cells by Bc1-2 and X-linked inhibitor of apoptosis.  Hum Immunol, 66:274-84. 

Emamaullee, J., A.M., P. Liston, R.G. Korneluk, A.M. Shapiro and J.F. Elliott (2005).  XIAP overexpression in islet b-cell engraftment and minimizes hypoxia-reperfusion injury.  American Journal of Transplantation, 5:1297-305.

Liu, Z., H. Li, M. Derouet , J. Filmus, E.C. Lacasse, R.G. Korneluk, R.S. Kerbel, and K. Rosen(2005).  RAS oncogene triggers upregulation of cIAP2 and XIAP in intestinal epithelial cells:  EGF receptor-dependent and –independent mechanisms of RAS-induced transformation.  J Biol Chem, 280:37383-92.

Plesner, A., P. Liston, R. Tan, R.G. Korneluk, and C.B. Verchere (2005). The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts.  Diabetes, 54:2533-2540.

Emamaullee, J.A., R.V. Rajotte, P. Liston, R.G. Korneluk, J.R. Lakey, A.M. Shapiro, and J.F. Elliott (2005).  XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes.  Diabetes 54:2541-2548.

Renwick, J., M.A. Narang, S.G. Coupland, J.Y. Xuan, A.N. Baker, J. Brousseau, D. Petrin, R. Munger, B.C. Leonard, W.W. Hauswirth, R.G. Korneluk and C. Tsilfidis (2006).  XIAP-mediated neuroprotection in retinal ischemia.  Gene Therapy, 13:339-47.

Conte, D., M. Holcik, C.A. Lefebvre, E. LaCasse, D.J. Pickets, K.E. Wright, and R.G. Korneluk (2006).  Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival.  Molecular and Cellular Biology, 26:699-708.

Cheung, H.H., L. Kelly, P. Liston, and R.G. Korneluk.  Involvement of caspase-2 and Caspase-9  in endoplasmic reticulum stress-induced apoptosis:  a role for the IAPs.  Experiment Cell Research, 312:2347-57.

Cheung, H.H., E.C. LaCasse and R.G. Korneluk (2006).  XIAP antagonism:  strategies in cancer treatment.  Clinical Cancer Research, 12:3238-42.

Shafey, D., R.G. Korneluk, and M. Holcik (2006).  Distinct patterns of expression of the inhibitor of apoptosis protein cIAP2 during murine embryogenesis.  Apoptosis, 11:1257-9. 

Liu, Z., H. Li, X. Wu, B. Hoon Yoo, S.R. Yan, A.W. Stadnyk, T. Sasazuki, S. Shirasawa, E.C. LaCasse, R.G. Korneluk and K. Rosen (2006).  Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells.  Oncogene, 25:7680-90.

Baird, S.D., M. Turcotte, R.G. Korneluk and M. Holcik (2006).  Searching for IRES.  RNA, 12:1755-85.

Micali, O.C., H.H. Cheung, S. Plenchette, S.L. Hurley, P. Liston, E.C. LaCasse, and R.G. Korneluk (2007).  Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-b.  BMC Cancer, 7:52.

Leonard, K.C., D. Petrin, S.G. Coupland, A.N. Baker, B.C. Leonard, E.C. LaCasse, W.W. Hauswirth, R.G. Korneluk and C. Tsilfidis (2007).  XIAP protection of photoreceptors in animal models of retinitis pigmentosa.  Plos ONE, 21:2:e314.

Hunter, A., E.C. LaCasse, and R.G. Korneluk (2007).  IAP targeting in the treatment of cancer. The Inhibitors-of-apoptosis (IAPs) as Cancer Targets.  Apoptosis,  12:1543-1568.

Plenchette, S., H.H. Cheung, W.G. Fong, E.C. LaCasse and R.G. Korneluk (2007).  The role of XAF1 in cancer.  Current Opinion in Investigational Drugs, 8:469-476.

Arora, V., H.H. Cheung, S. Plenchette, O.C. Micali, P. Liston and R.G. Korneluk (2007).  Degradation of survivin by the XIAP-XAF1 complex.   J Bio Chem 282:26202-9.

Cheung, H.H., S. Plenchette, C.J. Kerns, D.J. Mahoney and R.G. Korneluk (2008).  The RING domain of cIAP1 mediates the degradation of RING-bearing IAPS by distinct pathways.  Molecular Biology of the Cell, In Press.

Mahoney, D.J., H.H. Cheung, R. Mrad, S. Plenchette, C. Simard, E. Enwere, V. Arora, T.W. Mak, E.C. LaCasse, J. Waring and R.G. Korneluk (2008).  TNFa-mediated NF-kB activation requires either cIAP1 or cIAP2.  Proceedings of the National Academy of Science, In Press.

HONOURS & AWARDS

• International Research Scholar, Howard Hughes Medical Institute, 01/08 (3^rd term)

• Biomedical Science Ambassador Award, Partners in Research and Friends of CIHR, 05/04

• Career Achievement Award, BioNorth, Ottawa Life Sciences, 11/03

• McLaughlin Medal of The Royal Society of Canada, 04/03

• International Research Scholar, Howard Hughes Medical Institute, 01/02  (2^nd term)

• MRC Senior Scientist, Medical Research Council of Canada, 07/98

• Fellow of the Royal Society of Canada, 11/98

• International Research Scholar, Howard Hughes Medical Institute, 03/97

• Researcher of the Year, University of Ottawa, 01/96

• Applied Research Award, Ottawa Life Sciences, 10/95

• MRC Scientist, Medical Research Council of Canada, 04/93

• 125^th Anniversary Commemorative Medal, Governor General of Canada, 06/93

• Faculty of Medicine Award of Excellence, University of Ottawa, 05/92

•  Fellow of the Canadian College of Medical Geneticists, 01/86

Laboratory Personnel

Research Associates

• Dr. Eric LaCasse

Post Doctoral Fellows

• Dr. Herman Cheung

• Dr. Douglas Mahoney

• Dr. Stephanie Plenchette

Graduate Students

• Emeka Enwere

• Rim Mrad

• Audrey Brewster

Technologists

• Lynn Kelly

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