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MicroRNA regulation of Th17 cell differentiation

MicroRNA对Th17细胞分化的调节

基本信息

批准号：
9053230
负责人：
Misty Marie Montoya
金额：
$ 3.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-10 至 2017-12-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053230
关键词：
Adult Affect Anti-Bacterial Agents Antifungal Agents Asthma Autoimmune Diseases CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Cellular biology Chronic Data Development Disease Dose Event Exhibits Extrinsic asthma Family Flow Cytometry Future Gene Expression Gene Expression Regulation Gene Targeting Genes Goals Helper-Inducer T-Lymphocyte Human Human Biology Immune Immune response Immunity In Vitro Individual Inflammatory Inflammatory Response Interleukin-17 Knock-out Knockout Mice Literature Lung Mediating MicroRNAs Modeling Molecular Monitor Mus Ovalbumin Pathogenesis Patients Phenotype Physiological Play Post-Transcriptional Regulation Public Health Published Database Regulation Research Role T cell differentiation T-Lymphocyte Testing Tissues Transgenic Mice United States Untranslated RNA Work airway inflammation asthmatic airway asthmatic patient base chemokine receptor cytokine extracellular immune function improved outcome in vivo inhibitor/antagonist insight mouse model network models novel public health relevance reconstitution transcription factor

项目摘要

DESCRIPTION (provided by applicant) Asthma is a chronic inflammatory airway disease currently affecting 1 in 12 adults in the United States. T helper (Th) cells are immune cells that orchestrate the lung inflammatory response in asthma through secretion of inflammatory cytokines and recruitment of other immune cells. While the Th2 subset of cells has been most commonly studied in asthma, Th17 cells have also been implicated in disease pathogenesis in at least some subtypes of asthma. Th17 cells mediate anti-bacterial and anti-fungal immunity and they are clearly associated with autoimmune diseases, but their precise role in the pathogenesis of asthma remains poorly understood. The proposed work aims to elucidate the regulation of Th17 cells by microRNAs (miRNAs) to gain a better appreciation of their dysregulation in diseases such as asthma. miRNAs have emerged as important regulators of many aspects of immune cell differentiation and function. The cell fate decisions of activated T helper cells are particularly sensitive to precise dosing of regulatory factors, and are therefore subject to regulation by the fine-tuning activity of miRNAs. Recent work has shown that the miR-17~92 cluster restrains the expression of subset-inappropriate genes in T follicular helper (TFH) cells. In contrast, how miR-17~92 regulates the differentiation and function of Th17 cells remains unknown. The major goal of this work is to define the role of the miR-17~92 cluster in Th17 cell differentiation in vitro and its potential functional significance in asthma using airway inflammation models. Aim 1 will combine the use of miR-17~92 conditional knockout mice and manipulation of individual miRNAs within the cluster to clarify the role of these miRNAs in regulating Th17 cell differentiation in vitro and by the examination of Th17 resident tissues in vivo. Preliminary data suggests that miR-17~92 inhibits Th17 cell differentiation, which is opposite to its effects in Th1, Th2, and TFH cells. Aim 2 will assess the mechanisms by which miR-17~92 cluster miRNAs target gene expression networks that control Th17 cell biology. Finally, Aim 3 will determine the impact of miRNA regulation of Th17 cells in asthma using airway inflammation models. This work will provide valuable insights into the molecular events that govern Th cell fate decisions and plasticity and its impact in a common chronic inflammatory disease. Additionally, this work may help identify more specific treatments and improve outcomes for patients with sub-phenotypes of asthma where Th17 cells play a significant role in the inflammatory response.