Grant: Foundation Grant

<html> <body> <p>Crohn&rsquo;s disease (CD) is a chronic inflammatory disease of the intestine and affects over 150,000 Canadians. While current therapies target inflammation, there is no cure for CD. Continued basic research is needed to define disease mechanisms, to uncover new targets for therapy and to find a cure for this increasingly prevalent disorder.<br> <br> The <strong>overarching theme</strong> of my research program is to understand the pathogenesis of CD, with a specific interest into how dysregulation of innate immune responses may impact disease development. Over the past 13 years, my group has focused on the NOD-like receptor (NLRs) family of innate immune receptors, with a specific interest into understanding how these proteins defend the body against infection and how they regulate immune homeostasis at the level of the intestinal mucosa. <em>NOD2</em> is the strongest genetic link for the development of CD and together with another CD-associated gene, <em>ATG16L1</em>, we found that these proteins regulate the autophagy pathway, defend against bacterial infection and modulate the inflammatory response. Failure to regulate these processes is likely a key underlying trigger for CD but the molecular mechanisms at play as well as the nature of the affected cell populations remain unclear.<br> <br> Our studies funded over the last five years through two active CIHR operating grants and a Crohn's and Colitis Canada/Vertex pharmaceuticals grant form the basis of this new research program. We will explore two inter-related hypotheses that CD pathogenesis stems from i) intestinal epithelial cell (IEC) dysfunction and ii) an inappropriate interaction between the microbiota and/or particular microbes with IECs. Our approach will combine mouse genetic models that mirror human CD heritable risk, in vitro cell assays, as well as model systems using primary human IECs to translate basic findings and perform pre-clinical screens. The <strong>impact</strong> of this work will be the elucidation of fundamental mechanisms underlying CD pathogenesis and the potential to uncover novel drug targets that are at the root cause of inflammation in the intestine.</p> <p> <br> This current research proposal is underpinned by my expertise in mucosal immunology and cell biology, mouse models of infections and intestinal disease and studies of the gut microbiota. I have a network of local scientists and clinician scientists who will act as program experts by providing clinical samples, expertise in pathological analyses, microbiota meta-genomic and meta-transcriptomic analyses. The University of Toronto and affiliated hospitals as well as the Host-Microbiome Research Network, where I am the co-director, offer a rich environment with outstanding core facilities including gnotobiotic mouse housing, anaerobic microbial culturing, and state-of-the-art microscopy and flow cytometry.<br> <br> I have an excellent team of well-trained scientists and I am committed to their professional development. I have an excellent track record of mentoring trainees; a number of my former laboratory members have gone on to academic positions at prestigious universities. Trainees in my group benefit from the exposure to diverse technical approaches, the ability to collaborate with local experts and the possibility to present their work at international meetings. Moreover, their experience is enriched through the many offerings of the Department of Immunology, including seminar programs, social engagements, outreach and career development activities.</p> </body> </html>