Role of miRNAs in Th2-Driven inflammation in Asthma

miRNA 在 Th2 驱动的哮喘炎症中的作用

基本信息

批准号：
8309235
负责人：
Karl Mark Ansel
金额：
$ 18.01万
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：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309235
关键词：
3&apos Untranslated Regions Address Adrenal Cortex Hormones Allergic inflammation Asthma Basic Science Biological Assay Biological Process Biology Blood Bone Marrow Stem Cell Breathing Bronchial Lavages CD4 Positive T Lymphocytes Cell Separation Cell physiology Cells Chimera organism Chronic Clinical Clinical Trials Data Defect Development Disease Emerging Technologies Exhibits Family Gene Expression Genomics Health Helper-Inducer T-Lymphocyte Hematopoietic House Dust Mite Allergens Human In Vitro Individual Inflammation Intranasal Administration Knockout Mice Lead Lung Mediating Messenger RNA Methods MicroRNAs Microfluidics Modeling Molecular Molecular Profiling Mus Pathogenesis Pathology Pathway interactions Patients Pattern Process Production Public Health RNA Reporter Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sampling Screening procedure Sorting - Cell Movement Steroids Subgroup T cell differentiation T-Cell Proliferation T-Lymphocyte Testing Th1 Cells Th2 Cells allergic airway inflammation base cell behavior cytokine design functional genomics in vivo inhibitor/antagonist loss of function molecular phenotype mouse model nanolitre novel novel strategies novel therapeutic intervention optimism overexpression reconstitution research study respiratory response tool

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic respiratory condition characterized by allergic inflammation of the airways. T helper type 2 (Th2) cells coordinate and amplify allergic inflammation through the secretion of cytokines. The proposed studies address the central hypothesis that microRNAs (miRNAs) expressed by helper T cells regulate cellular functions that contribute to asthma pathology. miRNAs are endogenously expressed ~21nt RNAs that regulate gene expression. It is known that T cells that cannot form any mature miRNAs exhibit defects in proliferation, survival, cytokine production, and differentiation into Th1 and Th2 effector subsets. The challenges that remain are to identify the particular miRNAs that regulate each of these processes, to define their relevance to T cell functions in asthma, and to determine the messenger RNA targets through which these miRNAs mediate their effects. In Specific Aim 1, we will apply recently developed tools for delivering miRNA mimics and inhibitors into primary mouse and human T cells to perform functional screens that will identify miRNAs that regulate helper T cell functions relevant to asthma. The experiments proposed in Aim 2 will utilize a novel approach for miRNA expression profiling in limiting quantities of starting RNA to discover asthma-associated T cell miRNA expression patterns in clinical samples from highly characterized asthma patient subgroups, and to relate those patterns to clinical features and Th2-associated molecular phenotypes of disease. In Aim 3, we will characterize the mRNA targets and in vivo function of select miRNAs using genomics and detailed molecular analyses as well as mouse models of asthma. These studies will focus first on 3 strong candidate miRNAs identified in preliminary functional screens and expression profiling.

描述（由申请人提供）：哮喘是一种慢性呼吸道疾病，其特征是气道过敏性炎症。 2 型辅助 T (Th2) 细胞通过分泌细胞因子来协调和放大过敏性炎症。拟议的研究解决了一个中心假设，即辅助 T 细胞表达的 microRNA (miRNA) 调节有助于哮喘病理的细胞功能。 miRNA 是内源表达的 ~21nt RNA，可调节基因表达。众所周知，不能形成任何成熟 miRNA 的 T 细胞在增殖、存活、细胞因子产生以及分化为 Th1 和 Th2 效应子亚群方面表现出缺陷。剩下的挑战是确定调节每个过程的特定 miRNA，确定它们与哮喘中 T 细胞功能的相关性，并确定这些 miRNA 介导其作用的信使 RNA 靶点。在具体目标 1 中，我们将应用最近开发的工具将 miRNA 模拟物和抑制剂传递到原代小鼠和人类 T 细胞中，以进行功能筛选，从而识别调节与哮喘相关的辅助 T 细胞功能的 miRNA。目标 2 中提出的实验将利用一种在有限数量的起始 RNA 中进行 miRNA 表达谱分析的新方法，以发现来自高度特征化的哮喘患者亚组的临床样本中与哮喘相关的 T 细胞 miRNA 表达模式，并将这些模式与临床特征和临床特征联系起来。 Th2 相关疾病的分子表型。在目标 3 中，我们将使用基因组学和详细的分子分析以及哮喘小鼠模型来表征 mRNA 靶点和选定 miRNA 的体内功能。这些研究将首先关注在初步功能筛选和表达谱分析中鉴定出的 3 个强有力的候选 miRNA。