Project 455111

Crohn's disease (CD), is an inflammatory bowel disease (IBD) that adversely impacts the quality of life with severe clinical symptoms, including abdominal pain, diarrhoea, bloating, fatigue and fever. Canada has one of the highest reported prevalence and incidence rates of CD worldwide and >30% of CD-patients develop a narrowing of the intestine as a consequence of fibrosis and often require surgery due to intestinal blockage. Subsequently, these patients are predisposed to colitis-associated colorectal cancer (CAC). Currently, there is no effective therapy to cure fibrosis and hence, there is an unmet medical need to better understand how fibrosis develops in CD patients. CD-associated fibrosis likely stems from factors including host genetics, the immune system, the gut microbiota and the environment. Among genetic mutations, nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is the first and still remains the strongest genetic risk factor contributing to CD. NOD2 is an immune receptor that detects bacterial peptidoglycan and plays a crucial role in the maintenance of intestinal homeostasis. In particular, NOD2 genetic variations (R702W, G908R, L1007fsinsC) are found in about 30-50% of all the patients with CD and single NOD2 variants increase the risk for intestinal fibrosis by 8% and can go up to 41% for patients with two NOD2 variants. In this research proposal, using genetics, biochemistry, and systems biology tools, our objective is to develop an animal model and to investigate the biological processes that connect NOD2-associated genetic variants with the molecular and cellular mediators, leading to intestinal fibrosis. Significance: The objectives outlined in this research proposal will deepen our understanding of the pathobiology of CD-associated intestinal fibrosis. Our investigation will highlight new avenues and potential strategies to treat and prevent intestinal fibrosis.