Mechanistic studies of Interleukin 10 gene regulation in intestinal CD4 T cells

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DESCRIPTION (provided by applicant): Inflammatory Bowel Diseases (IBD), including Crohn's Disease and Ulcerative Colitis, result from complex interactions between host and environment leading to an excessive inflammatory response to the intestinal microbiota. Although several immunomodulatory therapies exist, many patients still experience a severe burden of disease. Due to the fact that the incidence of IBD is increasing both in North America and abroad, new therapeutic avenues are needed to more successfully treat these disorders. Interleukin-10 is a dimeric cytokine with potent anti-inflammatory functions in vivo. This is especially true in the intestinal tract, where IL-10 is essential to prevent excessive enteric inflammation in both mice and humans. However, modulating IL-10 production clinically has been hampered by a lack of understanding of the complexity of IL10 gene regulation. Here, we provide preliminary evidence that the transcriptional repressor Gfi1 acts to repress Il10 transcription in multiple lineages of CD4+ T cells. Furthermore, we show that Gfi1 deficient T cells do not drive severe disease in the CD45RBhi transfer model of colitis. Building on this preliminary work, we first propose to determine the mechanism of Gfi1 regulation of Il10 in CD4+ T cell subsets using a combined approach of gene and protein expression analysis, bioinformatics, and ChIP studies. Secondly, we will identify if the effect on Il10 is the protectiv mechanism in mouse models of IBD, and which T cell subsets contribute to this protection. The training program, sponsored by Dr. Casey Weaver, will allow for the learning of a variety of techniques in immunology, genetics, and IBD-directed research. Additionally, it will allow for scientific project design, communication, and training that will be beneficial for a career as a physician-scientist. While this project will investigate the regulation of Il10 by the use of mous models, our molecular studies will be guided by data from GWAS of humans with IBD. Thus, it should also shed light on IL10 regulation in human disease.