Microbial-derived factors regulating mucosal wound healing

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PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) currently afflicts more than 3.1 million people in the U.S. with over 100,000 new cases each year. Patients with IBD experience persistent and relapsing gastrointestinal tract inflammation causing abdominal pain, bleeding, diarrhea, and weight loss. The etiology of IBD, while unknown, centers around the loss of intestinal barrier integrity, and comprises both genetic and environmental factors, with emerging significance of shifts in the gut microbiota. Intestinal epithelial cells (IECs) form the dynamic barrier isolating the host immune system from the external environment. Rapid wound healing after the repeated damage and barrier disruption seen in IBD is crucial to inflammatory resolution. An established role of the microbiota is production of energy in the form short-chain fatty acids (SCFAs), such as butyrate. Decreases in butyrate-producing species are strongly associated with IBD. Preliminary studies show that butyrate augments barrier formation and enhances epithelial wound healing following injury. An unbiased single cell sequencing screen revealed that butyrate induces IEC expression of synaptopodin (SYNPO), an actin-associated protein previously uncharacterized in the intestinal epithelium. This proposal will test the hypothesis that the microbial-derived SCFA butyrate promotes intestinal wound healing and barrier through coordination of SYNPO expression and function in the context of inflammation resolution as well as homeostatic maintenance. Three specific aims will guide this project. Aim 1 will define the mechanisms of SYNPO regulation by SCFAs, including butyrate, through cell culture and promoter reporter analysis. Aim 2 will elucidate the functional role of SYNPO in IECs utilizing knockdown and overexpression cells and immunofluorescence. Aim 3 will determine the contribution of SYNPO in health and during mucosal disease using murine colitis models. Successful completion of this work will establish a critical role for the microbiota in regulating wound healing and ultimately recovery from IBD through a novel target, SYNPO. Understanding the mechanisms through which butyrate repairs tissue damage and restores the intestinal barrier will contribute to current therapeutic approaches. This comprehensive research training plan will provide outstanding mentorship with an experienced sponsor in the ideal environment of a rigorous basic science lab that is well-integrated clinically with the necessary resources for completing each aspect of this project. This includes a distinct mentorship team within the Mucosal Inflammation Program in addition to the guidance of the applicant’s thesis committee. This training will foster the applicant’s research and academic skills to pursue cross-cutting molecular level science that will advance therapeutics for tissue damage repair and novel disease target identification. These mechanistic studies hold translational potential to improve the quality of life for IBD patients and provide the optimal progression towards a career balancing biomedical research and clinical practice as a physician scientist.