Project 467186

Inflammatory bowel disease (IBD) is a chronic, debilitating condition which affects thousands of Canadians yearly and for which there are few long-termed therapies. This holds especially true for patients afflicted with fibrostenotic IBD, such as ulcerative colitis (UC) and Crohn's disease (CD), who often suffer from intestinal strictures due to fibrosis. The development of fibrosis and intestinal strictures found in fibrostenotic IBD, and in turn, the mechanisms underlying potential fibrosis reversal is poorly understood and so far has been largely, inadequately modeled in mouse models. Recently, our lab discovered that mice lacking the protein Fam105a (Fam105a-/- ) recapitulated human IBD phenotypes. Moreover, in collaboration with Dr. Aleixo Muise, we have identified familial pediatric IBD patients carrying FAM105A variants. Excitingly, both homozygous and heterozygous Fam105a mice exhibited intestinal fibrosis and strictures - a phenotype that has been rarely reported in mouse IBD models to date. This unique mouse IBD model provides us with a novel opportunity to conduct translational therapeutic research in fibrostenotic IBD. We will extensively analyze primary causal fibrotic events and cell types that drive Fam105a dependent intestinal fibrosis. This will be conducted through the visualization of immunofluorescence markers targeting cell proliferation, cell death and subcellular intestinal populations that have been previously shown to be dysregulated in human IBD and CD patient and mice samples. Ultimately, this characterization will help us design an approach to test whether Fam105a reactivation or the knockout of Fam105a targeted cell types can halt or reverse fibrosis.