Grant: Project Grant

Crohn's disease (CD) is a subset of IBD that affects 1 in 150 Canadians and requires hospitalization and surgical intervention in extreme cases. CD, unlike ulcerative colitis (UC), may affect any part of the GI tract with a predilection for the distal ileum, and causes a patchy pattern of inflammation extending through the thickness of the bowel wall. Mutations in various genes have been shown to correlate with IBD. However, these do not always seem to result in disease progression. Recently, genome-wide association studies have identified that additional mutations in four distinct genes correlate to Crohn's disease progression. Mutation in FoxO3a gene has been identified as one of those disease progression genes. It is not known how a mutation in FoxO3a correlates to aggressive disease. We have developed an experimental model wherein inactivation of both the disease susceptibility gene (IL-10) and the disease progression gene (FoxO3a) results in aggressive, spontaneous Crohn's disease. Preliminary results indicate that there are potent changes in the gut microbiome and the inflammatory response in the gut of FoxO3a-IL-10 double-deficient mice. In this proposal, we aim to identify how inactivation of FoxO3a influences Crohn's disease progression. We believe that by understanding the role of FoxO3a in the gut, our studies will open up new avenues for therapy.