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Scientific Centres
Solange Gauthier Karsh Laboratory
(Molecular Genetics Research)
Robert
Korneluk, Ph.D.
Director,
Solange Gauthier Karsh Laboratory
Children’s Hospital of Eastern Ontario
Director,
Apoptosis Research Center
Children’s Hospital of Eastern Ontario
Professor,
Department of Paediatrics and Department of Biochemistry,
Microbiology and Immunology, Faculty of Medicine, University
of Ottawa
Tel: (613) 738-3281
Fax: (613) 738-4833
E-mail
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
Liston, P., N. Roy, K. Tamai, C. Lefebvre, S. Baird, G.
Cherton-Horvat, R. Farahani, M. McLean, J-E Ikeda, A.E. MacKenzie
and R.G. Korneluk (1996). Suppression of
apoptosis in mammalian cells by NAIP and a related family
of IAP genes. Nature 379:349-353.
Waring, J.D., R. Haq, K. Tamai, L.A. Sabourin, J-E. Ikeda
and R.G. Korneluk (1996). Investigation of
Myotonic Dystrophy Kinase Isoform Translocation and Membrane
Association. J. Biol. Chem. 271(25):15187-15193.
Korneluk, R.G. and M.A. Narang (1997). Anticipating
Anticipation. Nature Genet. 15:119-120.
Liston, P., C. Lefebvre, W.G. Fong, J.Y. Xuan and R.G.
Korneluk (1997a). Genomic characterization of the
mouse inhibitor of apoptosis protein-1and 2 genes. Genomics
46:495-503.
Liston, P., S.S. Young, A.E. MacKenzie and R.G. Korneluk
(1997). Life and death decisions: the role of the IAPs in
modulating programmed cell death. Apoptosis 2:423-441.
Sabourin, L.A., K. Tamai, C.J. Storbeck, E.J. Whiting and
R.G. Korneluk (1997). Over-expression of
the myotonic dystrophy kinase (DMK) 3’ untranslated
region inhibits myoblast terminal differentiation in vitro.
J Biol Chem 272(47):29626-29635.
Xu, D.G., R.G. Korneluk, K. Tamai, M. Ikeda,
J-E. Ikeda, N. Wigle, A.M. Hakim, A. MacKenzie, and G.S. Robertson
(1997). Distribution of NAIP-like immunoreactivity in the
rat central nervous system. Journal of Comparative Neurology
381:1-13.
Xu, D.G., S.J. Crocker, J-P. Doucet, M. St-Jean, K. Tamai,
A.M. Hakim, J-E. Ikeda, R.G. Korneluk, A.
MacKenzie, and G.S. Robertson (1997). Elevation of neuronal
expression of NAIP reduces ischemic damage in the hippocampus.
Nature Medicine 9(3):997-1004.
LaCasse, E.C., Baird, S., Korneluk, R.G.
and A.E. MacKenzie (1998) The inhibitors of apoptosis (IAPs)
and their emerging role in cancer. Oncogene 17:3247-3259.
Storbeck, C., L. Sabourin and R.G. Korneluk
(1998). Definition of regulatory sequence elements in the
promoter region and the first intron of the Myotonic Dystrophy
Kinase (DMK) gene. J Biol Chem 273(15):9139-9147.
Wang, C-Y, M.W. Mayo, R.G. Korneluk, D.V.
Goeddel and A S. Baldwin, Jr (1998). NF-kB antiapoptosis:
induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress
caspase-8 activation. Science 281:1680-1683.
Holcik, M., C. Lefebvre and R.G. Korneluk
(1999). A new internal-ribosome-entry-site (IRES) motif potentiates
XIAP mediated cytoprotection. Nature Cell Biology 1:190-192.
Xu, D., Y. Bureau, D.C. McIntyre, D.W. Nicholson, P. Liston,
Y. Zhu, W-G Fong, S.J. Crocker, R.G Korneluk
and G.S. Robertson (1999). Attenuation of ischemia-induced
cellular and behavioral deficits by XIAP overexpression in
the rat hippocampus. J. Neurosci. 19:5026-5033.
Young, S.S., M.C. Lagace, C. Lefebvre, P. Liston and R.G.
Korneluk (1999). Genomic organization and physical
map of the human inhibitors of apoptosis: Hiap-1 and Hiap-2.
Mammalian Genome 10:44-48.
Fong, W-G., P. Liston, M. St.Jean, C. Craig and R.G.
Korneluk (2000) Expression and genetic analysis of
XIAP associated factor 1 (XAF1) in cancer cell lines. Genomics
70:113-122.
Holcik,
M., C.S. Thomson, Z. Yaraghi, C.A. Lefebvre, A.E. MacKenzie
and R.G. Korneluk (2000). The hippocampal neurons of Neuronal
Apoptosis Inhibitor Protein (NAIP) deleted mice display increased
vulnerability to kainic-acid induced injury. Proc Natl Acad
Sci USA 97:2286-2290.
Holcik, M. and R.G. Korneluk (2000). Functional
characterization of the X-linked Inhibitor of Apoptosis (XIAP)
IRES element: the role of La auotantigen in XIAP translation.
Molec. Cell. Biol. 20:4648-4657.
Holcik, M., N. Sonenberg, and R.G. Korneluk
(2000). Internal ribosome initiation of translation and the
control of cell death. Trends Genet. 10:469-473.
Holcik, M., C. Yeh, R.G. Korneluk and T.
Chow (2000). Translational upregulation of X-linked inhibitor
of apoptosis (XIAP) increases resistance to radiation induced
cell death. Oncogene 19:4174-4177.
Narang, M.A., J.D. Waring, L.A. Sabourin and R.G.
Korneluk (2000). Myotonic dystrophy (DM) protein
kinase levels in congenital and adult DM patients. Eur J Hum
Genet. 8:507-512.
Narang, M.A., J.D. Waring, L.A. Sabourin, E. Rajcan-Separovic,
D. Parry, F. Jirik and R.G. Korneluk (2000).
Skeletal Myopathy in mice over-expressing the human myotonic
dystrophy protein kinase (DMPK) gene. Gene Funct. Dis. 3:1-5.
Perrelet, D., A. Ferri, A.E. MacKenzie, G.M. Smith, R.G.
Korneluk, P. Liston, Y. Sagot, J. Terrado, D. Monnier
and A.C. Kato (2000). IAP family proteins delay motoneuron
cell death in vivo. Eur. J. Neurosci 12: 2059-2067.
Conte, D., P.Liston, J.W. Wong, K. Wright, and R.G.
Korneluk (2001) Thymocyte-targeted over-expression
of XIAP transgene disrupts T lymphoid apoptosis and maturation.
Proc. Nat. Acad. Sci (USA) 98:5049-5054.
Crocker, S.J., N. Wigle, P. Liston, C.S. Thompson, C.J. Lee,
D.G. Xu, S. Roy, D.W. Nicholson, D.S. Park, A. MacKenzie,
R.G. Korneluk and G.S. Robertson (2001) NAIP
protects the nigrostriatal dopamine pathway from intrastriatal
6-OHDA rat model of Parkinson’s disease. Eur J Neurosci
14:391-400.
Holcik, M., H. Gibson and R.G. Korneluk (2001)
XIAP: Apoptotic brake and promising therapeutic target. Apoptosis
4:253-261.
Lagace, M., J-Y Xuan, S. Young, C. McRoberts, J. Maier,
E. Rajcan-Separovic and R.G. Korneluk (2001)
Genomic organization of the X-linked inhibitor of apoptosis
and identification of a novel testis-specific transcript.
Genomics 77:181-188.
Liston, P., W-G. Fong, S. Toji, T. Miyazaki, N.L. Kelly,
K.T. Hicks, D. Conte, K. Tamai, G. Cherton-Horvat, C. Craig,
and R.G. Korneluk (2001). Identification
of XAF1 as an antagonist of XIAP anti-caspase activity. Nature
Cell Biol. 3:128-133.
Holcik, M., and R.G. Korneluk (2001) XIAP,
the guardian angel. Nature Reviews 2:550-556.
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.
Holcik, M., B.W. Gordon, T.A. Nevins, and R.G. Korneluk
(2002) The IRES-mediated translation of anti-apoptotic protein
XIAP is modulated by the heterogeneous nuclear ribonucleoproteins
C (hnRNPC1/C2) Mol. Cell. Biol., (in press).
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 (2002) Attenuation of MPTP-induced neurotoxicity
and behavioural impairment in NSE-XIAP transgenic mice. Neurobiol.
Disease, (in press).
Nevins, T.A., Z.M. Harder, R.G. Korneluk and
M. Holcik (2002) Distinct regulation of IRES-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. (in press).
Petrin, D., A. Baker, S.G. Coupland, P. Liston, M. Narang,
A. Timmers, W. Hauswirth, R.G. Korneluk,
and C. Tsilfidis (2002) Structural and functional protection
of photoreceptors from MNU-induced retinal degeneration by
the X-linked inhibitor of apoptosis (XIAP). IOVS (in press).
Honours & Awards
International Research Scholar, Howard Hughes Medical Institute,
01/02 (2nd 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
125th 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. Jamie Waring
Post
Doctoral Fellows
Dr. Herman Cheung
WaiGin Fong
Graduate
Students
Vinay Aurora
Stephen Baird
Damiano Conte
Allison Hunter
Mark Lagace
Technologists
Bingbing Han
Lynn Kelly
Christine McRoberts
Tara Nevins
Emma Tibbo
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