Role of SCGN in Intestinal Immune Homeostasis

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PROJECT SUMMARY I am an Assistant Professor in the Division of Pediatric Gastroenterology, Hepatology and Nutrition at The University of Texas Southwestern Medical Center. My long-term career goal is to become an independent researcher investigating genetic drivers of inflammatory bowel disease. Inflammatory bowel disease (IBD) is thought to result from critical environmental exposures in genetically susceptible individuals. However, much of the genetic susceptibility remains unaccounted for. In this regard, mechanistic studies of defined genetic variants associated with IBD can help us fill these critical gaps and may provide novel therapeutic targets. I have previously reported the identification of a mutation in the SCGN gene causing early-onset ulcerative colitis. SCGN encodes secretagogin, a calcium sensor exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons and participates in SNARE mediated secretion. The mutation identified in humans leads to abnormal SCGN-SNAP-25 membranous localization resulting in impaired hormone secretion, mimicking complete SCGN loss. Scgn deficiency in mice results in enhanced DSS colitis susceptibility. Our data suggests that the enteric nervous system might be responsible for the observed colitic phenotype. Subsequent preliminary data indicates that Scgn loss in mice results in hyperactivation of intestinal epithelial type I interferon response. The central hypothesis of this proposal is that neuroendocrine dysfunction resulting from SCGN deficiency plays a role in IBD pathogenesis through disruption of innate immune responses, specifically Type I interferon activation in the epithelium. The project’s overall goal is to study the role of SCGN in intestinal inflammation through the following specific aims: Aim 1 – To define the neuroendocrine lineage cells responsible for SCGN-dependent intestinal inflammation. Aim 2 – Determine the contribution of type I interferon signaling in SCGN-associated colitis susceptibility. Aim 3 – To identify SCGN-dependent immunoregulatory factors To carry out the work proposed in this mentored Career Development Award, I have developed a career development plan that takes advantage of the scientific environment at UTSW, with a specific focus on development of skills related to in-vivo models of intestinal inflammation and next-generation sequencing data analysis. I have brought together a mentorship/advisory committee composed of experienced clinical and basic science researchers with a focus on human genetics, intestinal inflammation and IBD. My main mentor, Dr. Ezra Burstein, leads this team. In summary, the information gained from the studies proposed here will shed light on the immune-regulatory role a group of cells not commonly thought to be key mediators of inflammation, have in the intestine, with the ultimate promise of propelling me towards independence.