PROJECT SUMMARY An impaired epithelial lining is a key pathological element of numerous diseases of the colon; however, our understanding of how specific epithelial cell populations contribute to colonic health and disease is limited. Deep crypt secretory (DCS) cells are a poorly-understood epithelial cell lineage residing at the colonic crypt base. These cells express immuno-modulatory, host defense, and stem cell niche factors that are commonly dysregulated in inflammatory bowel disease (IBD) and other disorders. Thus, DCS cells represent an appealing potential therapeutic target for restoring tissue health in colonic inflammatory disease. A better understanding of the basic biology of DCS cells is essential for future therapies targeting the epithelium. In recent work we found that immune signaling regulates DCS cell population size, and our preliminary data suggest that key inflammation-responsive factors drive DCS cells to an “activated” state characterized by heightened levels of immuno-modulatory and host defense factors. This project is designed to elucidate a novel paradigm of DCS cell activation in the response to colitis and to determine the role(s) of these cells in colonic inflammation and recovery. In the proposed work, we will 1) test whether impaired DCS cell responses exacerbate colonic inflammation and/or limit tissue repair and regeneration, 2) define the function of activated DCS cells in the colon, and 3) determine the cellular mechanisms that regulate DCS cell population shifts and activation. This investigation into the functional roles and regulation of DCS cells in colitis could point to new therapeutic targets for IBD and the promotion of intestinal health.