Our intestines comprise over 50% of our bodies immune cells and tightly maintains a constant state of homeostasis against foreign stimulus like food particles and bacteria. This immune ?tolerance? is broken during chronic intestinal inflammation as seen during inflammatory bowel diseases (IBD). Adverse CD4+ THelper responses perpetuate the chronic pathology observed in IBD, thus understanding the molecular mechanisms that control their function is central to endeavors of finding novel therapeutic treatments. A physiologic adaptive response to inflammation is a marked shift in the supply and demand of metabolites that results in limited oxygen availability (now termed inflammatory hypoxia) and activation of the transcription factors hypoxia- inducible-factors (HIFs). While there are multiple affects of hypoxia on T cell gene function, the effects on post- transcriptional regulation are underexplored. To investigate hypoxia-elicited tissue protective signaling we performed a screen of CD4+ T cell-specific miRNAs and identified a selective induction of miR-29a. Studies with genetic models identified a role of Hif-2? in miR-29a induction and subsequent experiments demonstrated repression of the miR-29a target-genes Tbet and IFN? (canonical TH1 markers) during hypoxia. Mice with a T- cell-intrinsic deficiency in Hif-2? displayed elevated Tbet levels in CD4+ T cells and exacerbated inflammation during experimental colitis. Based on these preliminary studies, we hypothesize that Hif-2? induction of miR- 29a suppresses TH1 CD4+ cell activation. In this proposal we will address this hypothesis with three integrated lines of investigation. Firstly, we will examine how Hif-2? transcriptionally induces miR-29a and the functional requirements for Hif-2? in CD4+ THelper differentiation. Second, we will assess the role of miR-29a in the regulation of T cell mediated colitis. Lastly, in proof of concept studies we will target miR-29a stabilization in vivo during experimental colitis. Collectively these studies aim to dissect the Hif-2?-miR-29a-Tbet axis in the regulation of CD4+ T cell-mediated intestinal inflammation.! !

Public Health Relevance

Auto-reactive CD4+ Helper T cell subsets play a central role in the pathogenesis of inflammatory bowel disease. The main goal of this research proposal is to understand how the inflamed intestine regulates CD4+ TH1 T cells via miRNAs. These studies will test how miR-29a tapers the inflammatory tone of gut-infiltrating CD4+ T cells during experimental inflammatory bowel disease (IBD). Our intended studies will provide novel insight into the endogenous microRNA-mediated mechanisms responsible for the regulation of adaptive immune responses in the intestine during IBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Perrin, Peter J
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University of Colorado Denver
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