MicroRNA-10a in Airway Smooth Muscle and Asthma

MicroRNA-10a 在气道平滑肌和哮喘中的作用

基本信息

批准号：
10062407
负责人：
Quan Lu
金额：
$ 50.46万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
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：
2018-01-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062407
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Adrenergic Receptor Agonist Albuterol Allergens Arrestins Asthma Bronchoalveolar Lavage Bronchodilator Agents Cell physiology Child Chronic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Development Down-Regulation Exhibits Exposure to Genes Genotype Glucocorticoids Human Inflammation Inflammatory Inhalation Knockout Mice Lung MAP3K7 gene Measures Mechanics MicroRNAs Molecular Mus Muscle Contraction Muscle function Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Population Publishing Pyroglyphidae Regulation Reporting Research Role Signal Transduction Small RNA Smooth Muscle Myocytes Techniques Testing Therapeutic Ubiquitination Wild Type Mouse Work airway hyperresponsiveness airway inflammation airway remodeling asthmatic asthmatic airway smooth muscle base chemokine cytokine experimental study genetic epidemiology genetic variant genome wide association study in vivo methacholine miRNA expression profiling mouse model new therapeutic target next generation sequencing novel overexpression precise genome editing rare variant reconstitution respiratory smooth muscle response transcriptomics

项目摘要

PROJECT SUMMARY Over 300 million people, many of them children, suffer from asthma. Airway smooth muscle (ASM) controls airway narrowing and plays a pivotal role in the pathogenesis of asthma. Asthmatic ASM becomes hyper-proliferative, secretes more inflammatory cytokines/chemokines and may be more contractile. These phenotypic changes in ASM contribute directly to airway remodeling and airway hyperresponsiveness (AHR)—cardinal features of asthma. Despite extensive studies on the regulatory mechanisms governing ASM phenotypes, no single gene or pathway is known to control multiple ASM phenotypes. Consequently, mainstay asthma therapies reduce either ASM contractility (-agonists) or airway inflammation (glucocorticoids), and there is no therapy that directly targets ASM proliferation. MicroRNAs are small yet powerful gene tuners: a single microRNA is capable of targeting a multitude of genes and thus has the potential to impact diverse cellular processes. We recently identified miR-10a as a highly ASM- enriched and the most abundant microRNA—accounting for more than 20% of total microRNA expression in the ASM. We have reported that miR-10a inhibits the proliferation of ASM cells by directly targeting PI3KCA--the central component of the PI3K pathway. Preliminary data indicate that miR-10a also suppresses NFB signaling while increasing the expression of 2-adrenergic receptor (2AR)—the target of mainstay asthma drug -agonists. Importantly, miR-10a expression is reduced in asthmatic ASM cells and by inflammatory cytokines. Based on these studies, we hypothesize that miR-10a regulates multiple critical ASM phenotypes via suppression of specific target genes and that perturbation of this regulation contributes to the development of asthma and alters response to asthma therapies. To test this hypothesis, we propose this highly integrative project that combines in vivo mouse models, molecular mechanistic studies in primary ASM cells, and genetic epidemiology in human asthma populations. Aim 1 will determine whether miR-10a inhibits AHR by suppressing ASM proliferation and chemokine secretion. Aim 2 will investigate whether that miR-10a augments bronchoprotection by inhibiting 2AR downregulation. Aim 3 will determine the association and function of miR-10a and target gene variants in asthma and in the response to asthma therapy. Results from this study will establish miR-10a as a master regulator of multiple critical ASM phenotypes and identify microRNA-10a as a novel therapeutic target for asthma.

项目概要超过 3 亿人（其中许多是儿童）患有气道平滑肌哮喘。 (ASM) 控制气道狭窄，在哮喘发病机制中发挥关键作用。哮喘 ASM 过度增殖，分泌更多炎症细胞因子/趋化因子 ASM 的这些表型变化可能会直接影响气道。重塑和气道高反应性（AHR）——哮喘的主要特征。对 ASM 表型调控机制的广泛研究，没有单一基因或已知该途径可控制多种 ASM 测试表型，即主要哮喘。疗法可减少 ASM 收缩力（ 激动剂）或气道炎症（糖皮质激素），目前还没有直接针对 ASM 增殖的治疗方法，MicroRNA 虽小但功能强大。基因调谐器：单个 microRNA 能够靶向多个基因，因此具有我们最近发现 miR-10a 是一种高度 ASM-的药物。富集且最丰富的microRNA——占总microRNA的20%以上我们报道了 miR-10a 通过抑制 ASM 细胞的增殖。直接靶向 PI3KCA——PI3K 通路的核心组成部分。 miR-10a 还抑制 NFβ 信号传导，同时增加 β2 肾上腺素能的表达受体 (2AR)——主要哮喘药物  激动剂的靶标，重要的是 miR-10a。基于这些，哮喘 ASM 细胞中的表达减少并受到炎症细胞因子的影响。研究中，我们发现 miR-10a 通过调节多种关键的 ASM 表型特定靶基因的抑制以及这种调节的扰动有助于影响哮喘的发展并改变对哮喘治疗的反应。假设，我们提出了这个高度综合的项目，结合了体内小鼠模型，原代ASM细胞的分子机制研究和人类遗传流行病学目标 1 将确定 miR-10a 是否通过抑制 ASM 来抑制 AHR。目标 2 将研究 miR-10a 是否会增强增殖和趋化因子分泌。通过抑制 2AR 下调来实现支气管保护，目标 3 将确定相关性和 miR-10a 和靶基因变异在哮喘和哮喘治疗反应中的功能。这项研究的结果将确立 miR-10a 作为多种关键 ASM 的主要调节因子表型并将 microRNA-10a 确定为哮喘的新治疗靶点。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CEBPD modulates the airway smooth muscle transcriptomic response to glucocorticoids.

DOI：
10.1186/s12931-022-02119-1
发表时间：
2022-07-28
期刊：
Respiratory research
影响因子：
5.8
作者：
通讯作者：

Drug Repurposing to Treat Glucocorticoid Resistance in Asthma.

DOI：
10.3390/jpm11030175
发表时间：
2021-03-03
期刊：
Journal of personalized medicine
影响因子：
0
作者：
Wang AL;Panganiban R;Qiu W;Kho AT;Chupp G;Meyers DA;Bleecker ER;Weiss ST;Lu Q;Tantisira KG
通讯作者：
Tantisira KG

A Long Noncoding RNA "lnc"ed to Asthma Genetics.