The role and regulation of deep crypt secretory cells in colitis

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PROJECT SUMMARY Deep crypt secretory (DCS) cells are an understudied lineage of secretory cells residing in the colonic crypt base with unknown roles in colitis. In preliminary data, I show that DCS cells express a class of proteins known as host defense peptides (HDPs) that can influence key epithelial (e.g. differentiation, barrier integrity) and immune functions. Despite clear demonstrations of altered colonic secretory cell numbers and HDP levels in inflammatory bowel disease (IBD), the mechanisms regulating DCS cells and HDPs are poorly understood. This proposal is designed to identify the mechanisms driving DCS cell differentiation and HDP production in colitis, and determine the role of these factors in regulating epithelial and immune functions. Using a mouse model with elevated DCS cell numbers, I am proposing coordinated in vivo and in vitro approaches to understand the mechanisms underlying DCS cell differentiation and HDP expression in the colon (Aim 1) and to test how altered DCS cell-derived HDPs affect colonic homeostasis and acute and chronic colitis severity (Aim 2). This work will be accomplished with new expertise obtained in advanced transcriptomic studies and epithelial lineage tracing in models of colitis by working with my team of co-mentors and advisory committee. This work will advance our understanding of the cellular mechanisms that drive intestinal epithelial remodeling in colitis, and thus may reveal new potential therapeutic targets for IBD and other intestinal inflammatory disease. The research and career development plan, generated in concert with my mentors and advisory committee, will provide the training and support necessary to become an independent investigator at an academic research institution.