GPR30-induced Tregs: a therapeutic approach to reversing colitis

University Of New Mexico Health Scis Ctr, Albuquerque NM

Investigators

Abstract

DESCRIPTION (provided by applicant): The G protein-coupled receptor GPR30 has been identified as a novel estrogen-binding receptor. Recent work has implicated GPR30 in estrogen-mediated immune regulation. Given the substantial evidence linking estrogen to autoimmune disease, I chose to investigate the role of GPR30 in the differentiation of CD4+ T cells, which are thought to play a central role in autoimmune pathogenesis. Preliminary studies have shown that GPR30 signaling enhances TGF(-induced development of an IL10 producing CD4+ T cell population that may suppress secretion of the proinflammatory cytokine IFN(. Evidence suggests these cells are in fact the hybrid CD4+IL10+IL17A+ regulatory T cell line that has recently emerged in the literature. Given the current evidence demonstrating IL10-mediated suppression of inflammatory bowel disease (IBD) and the evolving link between lL17, IFN(, and intestinal inflammation, I have developed the following hypothesis: GPR30 signaling drives the differentiation of an CD4+IL10+IL17+ regulatory T cell population that will localize to the gut mucosa to suppress T cell-mediated colonic inflammation. Aim1 will determine the role of GPR30 in the induction of regulatory T cell populations in culture (1.1-1.2) and their function in vivo within the mucosal immune system (1.3). Aim2 will investigate the GPR30-directed compound G-1 as a potenital therapeutic for IBD by evaluating effects on relevant T cell populations following systemic G-1 treatment (2.1) and the ability to reverse active colitis using a well established animal model of IBD (2.2). These experiments will lead to a better understanding of the role of estrogen in gut immune homeostasis and pathogenesis by investigating GPR30's role in CD4+ T cell differentiation within the mucosal immune system. In addition, my findings will determine the potential of GPR30-directed small molecules to reverse IBD-like intestinal inflammation.