Targeting intestinal epithelial endoplasmic reticulum stress and associated cell death in experimental models of inflammatory bowel disease

We and others have shown that the UPR is significantly activated in colonocytes found in inflammatory lesions in patients with IBD. However, to date, it is not clear whether increased epithelial cell death in IBD results from prolonged UPR responses or whether interfering with the UPR can diminish inflammation. The specific goals of the current proposal are:



- To determine the relationship between UPR activation, mode of epithelial cell death (apoptosis or necroptosis) and inflammation in acute and chronic mice models of enteritis (longitudinal) and in human biopsy samples (snapshot)

- To interfere with the UPR and/or cell death using validated compounds in different animal models. We will focus on possible cytoprotective effects of these compounds and use them to further elucidate the relationship between UPR activation, cell death and intestinal inflammation.

- To study epithelial functions of endoplasmic reticulum-resident aminopeptidase 1 (ERAP1), a candidate susceptibility gene for IBD that was recently identified in our lab and has important functions in the ER.