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.

项目摘要超过3亿人（其中许多孩子）患有哮喘。气道平滑肌（ASM）控制气道变窄，并在哮喘发病机理中起关键作用。哮喘ASM变得过度增长，秘密更多的炎性细胞因子/趋化因子并且可能更收缩。 ASM中的这些表型变化直接有助于气道重塑和气道高反应性（AHR） - 哮喘的心电特征。尽管关于管理ASM表型的调节机制的广泛研究，没有单个基因或已知途径可以控制多种ASM表型。因此，主要哮喘疗法可降低ASM收缩力（振剂）或气道注射（糖皮质激素），并且没有直接针对ASM增殖的疗法。 microRNA很小但功能强大基因调谐器：单个microRNA能够靶向多种基因，因此具有影响潜在的细胞过程的潜力。我们最近将miR-10a确定为高度ASM- 富集和最丰富的microRNA，占总microRNA的20％以上在ASM中的表达。我们报道了miR-10a抑制ASM细胞的增殖直接靶向PI3KCA - PI3K途径的中心部分。初步数据指示 miR-10a还抑制了NFB信号传导，同时增加了2-肾上腺素能的表达受体（2AR） - 主柱哮喘药物激动剂的靶标。重要的是，mir-10a 哮喘ASM细胞和炎症细胞因子中的表达降低。基于这些研究，我们假设miR-10a通过抑制特定靶基因的抑制和该调节的扰动有助于哮喘的发展并改变对哮喘疗法的反应。测试这个假设，我们提出了这个高度集成的项目，该项目结合了体内小鼠模型，原代ASM细胞中的分子机械研究和人类的遗传流行病学哮喘种群。 AIM 1将确定miR-10a是否通过抑制ASM抑制AHR 增殖和趋化因子分泌。 AIM 2将调查miR-10a是否增加支气管保护通过抑制2AR下调。 AIM 3将确定协会，并且 miR-10a和靶基因变异在哮喘和对哮喘治疗的反应中的功能。这项研究的结果将建立miR-10a作为多个关键ASM的主调节器表型并将microRNA-10A识别为哮喘的新型治疗靶标。

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.