Title:
Associate Professor

Institute:
University of Toronto

Department: 
Immunology

Province:
Ontario

Training:
Postdoctoral fellow, Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA
PhD, University of Toronto, Toronto, Ontario, Canada
MSc, University of Toronto, Toronto, Ontario, Canada
BSc, McGill University, Montreal, Quebec, Canada

Research interests:
B cells, mismatch repair, colon cancer

Recognitions and awards:
Canada Research Chair, 2009-2014
Canadian Society for Immunology New Investigator Award, 2008
CIHR New Investigator Salary Award, 2004

Research Projects

Project title:
Delineating the role of the mismatch repair pathway in suppressing colon carcinogenesis

Funding period:
2011-2013

Program:
Operating Grant (basic research)

Summary:
Colorectal cancer is the third most common type of cancer and the leading cause of cancer-related deaths. Specific mutations are linked to colorectal cancer development, and mutations in genes involved in mismatch repair are one of the most common types of genetic deficiencies that predispose to this type of cancer. The normal function of mismatch repair is to repair mutations produced during DNA replication. In the absence of mismatch repair, mutations accumulate throughout the genome. For colon cancer, mismatch repair deficiency has been suggested to lead to an increase in mutations in genes essential for normal colon cell growth. What is not clear is whether the mutations that are normally repaired by mismatch repair are produced during DNA replication or through some other source. In response to intestinal infection, immune cells produce nitric oxide at high levels. Relevant to this study, nitric oxide is a potent DNA mutagen that mutates the bacterial genome as well as the genome of colon epithelial cells. However, the mutations produced by nitric oxide have not been shown to be repaired by the mismatch repair pathway. Our hypothesis is that mutations produced by nitric oxide are normally repaired by the mismatch repair pathway, and in its absence, there is a catastrophic increase in genetic mutations. For this study, we will test the hypothesis that nitric oxide is released in response to intestinal bacteria and that this leads to the development of colon cancer in mismatch repair deficient mice. Mismatch repair deficient mice will be treated with oral antibiotics in their drinking water to reduce intestinal bacteria and their intestines will then be examined for colon cancer and for mutations in gut epithelial cells.  We will also inhibit the production of nitric oxide in mice and assess whether this chemical is directly responsible for colon cancer in this mouse model. This study will test the hypothesis that the mismatch repair pathway is the major DNA repair pathway for nitric oxide-induced DNA damage and that deficiency in mismatch repair predisposes to colorectal cancer development in response to the intestinal microflora.