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.
RELEVANCE: Autoimmune diseases occur when our body's natural defenses against invading pathogens attack healthy tissue, and are thought to afflict 3% of the population worldwide. Clinical and experimental evidence has led scientists to suspect that hormones such as estrogen can influence immune system physiology and the course of autoimmune diseases. This work attempts to target discrete effects of estrogen on critical gut immune cells to reverse the course of inflammatory bowel disease, a devastating autoimmune pathology of the gastrointestinal tract characterized by a miriad of severe symptoms and often leading to intestinal resections and cancer.