Functional role of hsa-miR-504 in airway inflammation and remodeling in asthma

hsa-miR-504 在哮喘气道炎症和重塑中的功能作用

• 批准号: 8803630
• 负责人: Jose Luis Gomez-Villalobos
• 金额: $ 13.89万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803630
• 关键词: Accounting; Address; Asthma; Base Sequence; Biological Assay; Biopsy; Blood Circulation; Bronchial Hyperreactivity; Cell Differentiation process; Cell Line; Cells; Chitinase; Chronic; Clinical; Cluster Analysis; Computer Analysis; Data Set; Development; Disease; Epithelial; Epithelial Cells; Evaluation; Family; Flow Cytometry; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Goals; Health Care Costs; Healthcare; Immunophenotyping; Impairment; In Situ Hybridization; Individual; Inflammation; Inflammatory; Lead; Lung diseases; Measures; Messenger RNA; MicroRNAs; Modeling; Molecular; Monitor; Multicenter Trials; National Heart, Lung, and Blood Institute; Nucleotides; Obstruction; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Population; Proteins; Protocols documentation; Pulmonary Function Test/Forced Expiratory Volume 1; Regulator Genes; Research; Respiratory physiology; Risk; Role; Severities; Source; Sputum; Subgroup; Susceptibility Gene; System; Tissues; Transcript; United States; abstracting; adverse outcome; airway inflammation; airway remodeling; base; cell type; cohort; genome-wide; health care service utilization; improved; macrophage; member; molecular phenotype; nano-string; novel; programs; therapeutic target

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperreactivity and airway inflammation that increasingly afflicts the United States population. Individuals with severe asthma, suffer the most and drive at least 50% of the healthcare costs due to asthma in the U.S. To improve our understanding of this and other subgroups of this disease, the NHLBI initiated the Severe Asthma Research Program (SARP). This program identified 5 subgroups of asthma with different phenotypic features, of these, cluster 5 is characterized by severe irreversible airflow obstruction indicatin that airway remodeling is a key feature that discriminates the most severe subgroups of disease. Many of the molecular mechanisms that underlie airway remodeling have not been clearly elucidated in individuals with asthma. One of the main barriers to the characterization of airway remodeling has been the lack of safe access to the airway tissue itself in individuals with severe airflow impairment. In an effort to define novel pathways associated with the pathobiology of airway remodeling in asthma, our research team at the Yale Center for Asthma and Airways Disease (YCAAD) has developed a non-invasive protocol to measure genome-wide gene expression in the sputum of individuals with asthma. To identify regulatory genes that are associated with the development of airway remodeling and its relation with SARP clusters, we determined the effect of expression of microRNAs (miRNAs) on airflow obstruction in the YCAAD dataset. Analysis of miRNA expression in cells isolated from induced sputum with the Affymetrix 1.0 ST microarray identified an inverse correlation between hsa-miR-504 and baseline forced expiratory volume in 1 second (FEV1). In addition, hsa-miR-504 correlated positively with sputum levels of YKL-40, a chitinase-like protein we have previously shown to be associated with airway remodeling and increased asthma severity. A computational analysis overlapping the predicted hsa-miR-504 targets with the sputum gene expression profile, identified 90 transcripts that are likely to be hsa-miR-504 targets when a False Discovery Rate (FDR <0.05) threshold is used. Based on these exciting findings, we hypothesize that changes in the expression of hsa-miR-504 are indicative of asthma severity and that these changes lead to distinct changes in the expression of genes important in persistent inflammation and airway remodeling. To address this hypothesis we will focus on the following specific aims: 1). Determine the relationship between sputum hsa-miR-504, asthma and asthma severity. 2). Determine the cellular sources, immunophenotype and biologic targets of hsa-miR-504 in the sputum of individuals with asthma. 3). Identify a severe asthma phenotype associated with hsa-miR-504 and monitor its impact on adverse outcomes and changes in lung function through the longitudinal evaluation of subjects with asthma. (End of Abstract)

描述(申请人提供)：哮喘是一种慢性呼吸道炎症性疾病，以支气管高反应性和呼吸道炎症为特征，越来越多地困扰着美国人。患有严重哮喘的人，遭受的痛苦最大，并在 在美国，至少50%的医疗费用是由哮喘引起的。为了提高我们对这种疾病和其他亚组疾病的了解，NHLBI发起了严重哮喘研究计划(SARP)。本程序确定了5个不同表型特征的哮喘亚组，其中5个亚组以严重的不可逆气流阻塞为特征，这表明气道重塑是区分最严重亚组的关键特征。在哮喘患者中，许多导致气道重塑的分子机制尚未明确阐明。描述气道重塑的主要障碍之一是在严重气流障碍的个体中缺乏安全的呼吸道组织本身。为了确定与哮喘气道重塑的病理生物学相关的新途径，我们在耶鲁大学哮喘和呼吸道疾病中心(YCAAD)的研究团队开发了一种非侵入性的方案，以测量哮喘患者痰中全基因组的基因表达。为了确定与气道重塑的发展相关的调控基因及其与SARP簇的关系，我们在YCAAD数据集中确定了microRNAs(MiRNAs)的表达对气流阻塞的影响。用Affymetrix 1.0ST微阵列分析诱导痰细胞中miRNA的表达，发现hsa-miR-504与基线1秒用力呼气量(FEV1)呈负相关。此外，hsa-miR-504与YKL-40的痰水平呈正相关，YKL-40是一种几丁质酶样蛋白，我们先前已证明与呼吸道重塑和哮喘严重程度增加有关。将预测的hsa-miR-504靶标与痰基因表达谱重叠的计算分析，确定了当使用假发现率(FDR&lt；0.05)阈值时可能是hsa-miR-504靶标的90个转录本。基于这些令人兴奋的发现，我们假设hsa-miR-504表达的变化预示着哮喘的严重性，并且这些变化导致在持续性炎症和气道重塑中重要的基因表达的明显变化。为了解决这一假设，我们将重点关注以下具体目标：1)。确定痰中hsa-miR-504与哮喘及哮喘严重程度的关系。2)。测定哮喘患者痰中hSA-miR-504的细胞来源、免疫表型和生物学指标。3)。通过对哮喘受试者的纵向评估，确定与hsa-miR-504相关的严重哮喘表型，并监测其对不良结局和肺功能变化的影响。(摘要结束)