Project 461936

Gut diseases have a huge impact on the Canadian health care system cost. Indeed, Canada has among the highest rates of intestinal inflammatory bowel diseases (IBD) in the world, with approximately 300 thousands of people affected causing a direct annual cost of 1.28 billion. The intestinal epithelium forms a barrier that protects the host and its immune system from luminal threats. It was confirmed that defects in this barrier play a major role in the progression of IBD. Thus, there is a strong need to identify therapeutic molecules designed to maintain epithelial barrier and limit inflammation in the hope to cure these devastating diseases. We have identified a central epithelial regulator that maintains barrier function and protect against IBD susceptibility. This regulator, named HNF4A, acts as a nuclear receptor that regulates the expression of the intestinal epithelial cell genome. We suspect this protein to restrain the inflammasomes-gasdermin D signaling pathway that was recently suggested to play a role in IBD. Gasdermin D forms a pore within the plasma cell membrane to allow the release of pro-inflammatory molecules. With the use of novel biological systems derived from mice, we expect to discover the biological relevance of HNF4A interaction with gasdermin D. This research will allow the discovery of alternative ways of improving therapeutic strategies against gut diseases. Since there are drugs already approved for the target of gasdermin D in other biological systems, this project offers the possibility to expedite preclinical testing to benefit IBD patients.