Inflammatory bowel disease (IBD) is an idiopathic disease of the colon and small intestine. The major types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). An estimated 1.4 million persons in the United States suffer from IBD. IBD causes severe diarrhea, abdominal pain and increases the risk of colorectal cancer. Importantly, there is no cure for IBD. Signal transducer and activator of transcription (Stat) 3 ha been shown to play a pathogenic role in mice models of IBD. Increased levels of activated Stat3 directly correlated with the degree of intestinal inflammation in humans with IBD. There are two isoforms of Stat3 (?/p92 and ?/p83). Mice expressing only Stat3? are hyper-responsive to bacterial LPS challenge and are resistant to hemorrhagic shock-induced apoptosis of parenchymal cells within the heart, lung, and liver suggesting that Stat3? attenuates inflammatory and anti-apoptotic responses mediated by Stat3?. We previously developed a potent, small-molecule Stat3 inhibitor (C188-9) that is selective for Stat3? vs. Stat3?. In preliminary studies, we demonstrated that C188-9 almost completely prevents dextran sodium sulphate (DSS)-induced colitis in mice. In the current proposal, we will use C188-9 and transgenic Stat3? mice to interrogate the hypothesis that Stat3? contributes to the pathogenesis of IBD and to establish proof-of-principle that IBD can be treated using selective pharmacological targeting of Stat3?. We have formulated 2 tightly focused aims to examine this hypothesis.
Specific aim 1 : To determine if IBD can be treated with C188-9, a small-molecule inhibitor of Stat3 that selectively targets Stat3?. We will determine if C188-9 is of benefit in 2 preclinical models of chronic IBD-IBD induced by DSS, which mimics UC, and IBD induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), which mimics CD. Endpoints that will be examined include mortality rate, weight loss, rectal bleeding, stool consistency, colon length and extent of colonic inflammation (as determined by histopathological assessment). We will also examine if the mechanism by which C188-9 inhibits the pathogenesis of IBD is through decreasing the production of proinflammatory cytokines and chemokines by immunocytes and/or through increased apoptosis of pathogenic CD4+T-cells.
Specific aim 2 : To determine the contribution of Stat3? to the pathogenesis of IBD. We will subject transgenic Stat3? knock-in/Stat?-deficient mice and their littermate WT controls to DSS- and TNBS-induced colitis and compare the severity of disease manifestations, levels of cytokines and chemokines and T-cell apoptosis as outlined in Aim 1. This proposal will provide support for the hypothesis that Stat3, particularly Stat3?, contributes to the pathogenesis of IBD and that targeting Stat3 with a small molecule inhibitor that is selective for Stat3? is a novel and effective approach to IBD treatment.
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, the major types of IBD are Crohn's disease and ulcerative colitis. The main objective of the current proposal is to study the role of STAT3, a transcription factor in pathogenesis of IBD and to determine if STAT3 inhibitors may be beneficial in IBD. This innovative proposal may lead to improvements in the therapy of IBD with STAT3 inhibitors, and has a strong potential of clinical applicability in the foreseeable future.
