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microRNA-dependent regulation of intestinal T-cells²

肠道 T 细胞的 microRNA 依赖性调节²

基本信息

批准号：
10311983
负责人：
Edwin Fulco de Zoeten
金额：
$ 34.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-13 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311983
关键词：
Acute Address Affect Attenuated Bacteria Binding Binding Sites Biological Assay CD4 Positive T Lymphocytes Cells Chronic Clinical Colitis Crohn&apos s disease Data Development Etiology Food Genes Genetic Models Genetic Transcription Goals Homeostasis Homing Hypoxia Hypoxia Inducible Factor Ileitis Immune Immune Tolerance In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Instruction Interferon Type II Intestines Investigation Link Mediating Messenger RNA Metabolic MicroRNAs Modality Molecular Mus Oxygen Pathogenesis Pathogenicity Pathology Pathway interactions Persons Pharmacological Treatment Physiological Play Post-Transcriptional Regulation Process Regulation Reporter Repression Research Proposals Role Signal Transduction Stimulus T cell regulation T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissues Transcriptional Activation Transcriptional Regulation Translating Treatment Protocols Ulcerative Colitis Untranslated RNA adaptive immune response autoreactivity base cell mediated immune response design effector T cell experimental study gene function gut inflammation in vivo indexing insight intestinal hypoxia mimetics nanoparticle delivery novel novel therapeutics overexpression particle promoter response targeted treatment transcription factor

项目摘要

Project Summary 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-2α in miR-29a induction and subsequent experiments demonstrated repression of the miR-29a target-genes Tbet and IFNγ (canonical TH1 markers) during hypoxia. Mice with a T- cell-intrinsic deficiency in Hif-2α displayed elevated Tbet levels in CD4+ T cells and exacerbated inflammation during experimental colitis. Based on these preliminary studies, we hypothesize that Hif-2α 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-2α transcriptionally induces miR-29a and the functional requirements for Hif-2α 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-2α-miR-29a-Tbet axis in the regulation of CD4+ T cell-mediated intestinal inflammation.! !

项目总结