Title:   
Scientist, Molecular Brain Research Group
Full Professor, Department of Biochemistry 

Institute:
University of Western Ontario, London

Department:  
Robarts Research Institute

Province:
Ontario

Training:  
Postdoctoral Fellow, Department of Neurobiology, Stanford University School of Medicine, Stanford, California, USA
PhD, Department of Molecular and Medical Genetics, formerly Medical Genetics and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
MSc, Department of Medical Genetics and Medical Biophysics, University of Toronto, Toronto, Canada
BSc, Honors Microbiology, University of Guelph, Guelph, Ontario, Canada

Research interests:
Neural tumors, Neurotrophin Signaling, Mechanisms of cell death  

Recognitions:
Premier’s Research Excellence Award
The EJLB Foundation, Scholarship Research Program
Medical Research Council of Canada, Scholarship Award 

Research Projects

Project title:
Mechanisms of Trk-Dependent Cell Death in Human Brain Tumors

Funding period:  
2010-2012

Program:
Operating Grant (Basic Research)

Summary:
Medulloblastomas are a childhood brain tumor that represent approx. 20% of pediatric brain tumors and account for ~3-4% of new cases and ~7% of cancer-related deaths in Canadian children each year (Canadian Cancer Statistics 2007). These tumors have been relatively difficult to treat based on their location, poor response to chemotherapy as well as a reluctance to use radiation due to secondary neurological effects.  We have identified a receptor based approach to stimulate a novel type of cell death in these tumors by a novel process in which the cells 'drink' fluid and small molecules from the media around it.  This is a process that occurs normally in many cell types but we have found that if it is over-stimulated, that it can induce cell death in this type of tumor as well as in glioblastomas, an aggressive brain tumor of adults.   This application will determine the mechanism of how this type of cell death is regulated and whether it can be stimulated by alternative approaches.

CRS publications:

Li, C., J.I.S. MacDonald, T. Hryciw and S.O. Meakin. 2010. Nerve Growth Factor Activation of the TrkA Receptor Induces Cell Death, by Macropinocytosis, in Medulloblastoma Daoy Cells.  Journal of Neurochemistry. 112: 882-899

Liu, H.Y, J. I. S. MacDonald, T. Hryciw, C. Li and S.O. Meakin. 2005. Tid1, a Human DNA J Domain Protein, Associates with Trk Receptor Tyrosine Kinases and Facilitates Neurotrophin-Induced Neurite Outgrowth. J. Biol. Chem. 280: 19461-19471.

Gryz, E.A. and S.O. Meakin. 2003. Acidic Amino Acid Substitution of the Activation Loop Tyrosines in TrkA Supports Nerve Growth Factor-dependent, but not Nerve Growth factor-independent, Differentiation and Cell Cycle Arrest in the Human Neuroblastoma cell line, SY5Y. Oncogene 22: 8774-85.

Gryz, E.A. and S.O. Meakin. 2000. Acidic Substitution of the Activation Loop Tyrosines in TrkA Supports Nerve Growth Factor -Independent Cell Survival and Neuronal Differentiation. Oncogene 19: 417-430.

MacDonald, J.I.S., E.A. Gryz, C. J. Kubu, J.M. Verdi and S.O. Meakin. 2000.  Direct
Binding of the Signaling Adapter Protein, Grb2, to the Activation Loop Tyrosines on the Nerve Growth Factor Receptor Tyrosine Kinase, TrkA.  J. Biol. Chem. 274: 18226-18233.

Meakin, S.O., J.I.S. MacDonald, E.A. Gryz, C.J. Kubu and J.M. Verdi. 1999. The Signaling Adapter Protein FRS-2 Competes with Shc for Binding to the Nerve Growth Factor Receptor, TrkA: A Model for Discriminating Proliferation and Differentiation. J. Biol. Chem. 274: 9861-9871.

Meakin, S.O., E.A. Gryz and J.I.S. MacDonald. 1997. A Kinase Insert Isoform of Rat TrkA supports Nerve Growth Factor Dependent Cell Survival but not Neurite Outgrowth. J. Neurochem. 69: 954-967.

Past CRS projects:

2006 TrkA Activation of autophagy in human neural tumours

2004 TRK activation of apoptosis in human neural tumors

2002 Neurotrophin activation of Tid1 in human neural tumors.

2000 Constitutively active TrkA signaling in human neural tumors:  Analysis of their potential therapeutic application.
 
1998 Construction of constitutively active TrkA receptor mutants and analysis of their potential therapeutic application.
 
1996 Novel intracellular targets of the TrkA protooncogene.