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: 9284521
• 负责人: Jose Luis Gomez-Villalobos
• 金额: $ 17.4万
• 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/9284521
• 关键词: 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; Genetic Transcription; 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; 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; adverse outcome; airway inflammation; airway remodeling; base; cell type; cohort; genome-wide; health care service utilization; improved; individual patient; macrophage; member; molecular phenotype; nano-string; novel; novel therapeutics; 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（由申请人提供）：哮喘是一种以支气管高反应性和气道炎症为特征的气道慢性炎症性疾病，越来越多地折磨着美国人群。患有严重哮喘的人遭受的痛苦最大，而且病情严重