权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional role of miR-511-3p in allergic asthma and its underlying mechanisms

miR-511-3p在过敏性哮喘中的功能作用及其潜在机制

基本信息

批准号：
10385822
负责人：
Peisong Gao
金额：
$ 62.31万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-07 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10385822
关键词：
Affinity Allergens Allergic Allergic inflammation Anti-Inflammatory Agents Antigens Asthma Binding Biotin Clustered Regularly Interspaced Short Palindromic Repeats Cost Measures Critical Care Data Set Defense Mechanisms Dependovirus Development Dictyoptera Economic Burden Environmental Exposure Equilibrium Exposure to Extrinsic asthma Genes Genetic Transcription Genome engineering Goals Human Hypersensitivity Immune response Inflammatory Inhalation Knock-out Knockout Mice Lead Link Longitudinal Studies Luciferases Lung Mannose Mediating Medicine Messenger RNA MicroRNAs Molecular Mus Patients Phenotype Pilot Projects Plasma Polysaccharides Prevalence Prostaglandin D2 Public Health Reporter Research Risk Role Sampling Severities Signal Pathway Signal Transduction Sputum TLR4 gene Testing Transcript Untranslated RNA airway hyperresponsiveness airway inflammation allergic airway inflammation asthma exacerbation asthma model asthmatic base cockroach allergen conditional knockout environmental allergen experimental study extracellular vesicles human subject innovation macrophage mannose receptor mouse model new therapeutic target novel novel diagnostics overexpression peripheral blood prophylactic tool transcriptomics

项目摘要

ABSTRACT Exposure to cockroach allergen can lead to allergic sensitization and an increased risk of allergic asthma. However, the underlying molecular mechanisms are currently not well-established. Our long-term goals are to elucidate the fundamental underlying mechanisms and identify novel therapeutic targets for allergic asthma. During the pilot studies, our group has made significant contributions to unraveling an important link between cockroach antigen and development of allergic asthma. Specifically, our profiling of N-linked glycans from cockroach allergen identified several major glycans with high affinity to mannose receptor, MRC1/CD206. Furthermore, we have identified a critical but previously unrecognized role of MRC1 in allergen clearance as a natural defense mechanism and in limiting the progression and severity of cockroach allergen-induced allergic inflammation in a mouse model of asthma. This occurs through alterations in macrophage clearance of the inhaled cockroach allergens and balance of M1/M2 macrophage polarization. This was at first perplexing because MRC1 lacks any known signaling motif, therefore, the signaling cascades of MRC1 in allergen-induced airway inflammation and macrophage polarization remain obscure. Our breakthrough for a deeper understanding of the MRC1 signaling pathway came with the recognition that a key regulatory miR-511-3p, encoded by both mouse and human MRC1 gene, is transcriptionally co-regulated with MRC1 in macrophages. These exciting findings lead us to propose a novel hypothesis that MRC1 is largely involved in allergen clearance as a natural defense mechanism, and MRC1-encoded miR-511-3p is involved in mediating MRC1 downstream immune responses and protecting against allergen-induced airway inflammation. This hypothesis is further buttressed by our recent findings that plasma levels of miR-511-3p were much lower in asthmatics compared to controls, and that adeno-associated virus (AAV)-mediated miR-511-3p over-expression ameliorated the allergen-induced airway inflammation in Mrc1-/- mice, but miR-511-3p knockout mice showed increased allergen-induced airway inflammation. These exciting data set the stage to critically evaluate the functional significance of miR-511-3p in allergic asthma and its underlying mechanisms. Three independent yet related specific aims are proposed. Aim 1 will determine the significance of miR-511-3p in allergic asthma by quantifying miR-511-3 in plasma, sputum and extracellular vesicles (EVs) from plasma and sputum of allergic asthmatics and testing its role in macrophage polarization and function. Aim 2 will define whether miR-511-3p protects against asthma using miR-511-3p global and macrophage conditional knockout mice (e.g., LysM-cre; miR-511-3pflox/flox) and mannose-decorated EV-miR- 511-3p-treated mice. Aim 3 will identify miR-511-3p targets by integrating gene profiling and our unique affinity- based transcriptomic approach for miR-511-3p binding partner mRNAs/long non-coding RNAs. Collectively, our studies will provide a conceptual framework linking allergens, MRC1, and miR-511-3p to key features of asthma. Ultimately, these studies may allow for the development of new diagnostic and therapeutic targets for asthma.

摘要