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Systems Biology of a MicroRNA Network in Neutrophilic Asthma

中性粒细胞性哮喘中 MicroRNA 网络的系统生物学

基本信息

批准号：
10033783
负责人：
Jose Luis Gomez-Villalobos
金额：
$ 66.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10033783
关键词：
Address Adrenal Cortex Hormones Affect Airway Disease Asthma Biological Cell Separation Cells Data Set Environment Epithelial Cells Foundations Future Gene Expression Gene Expression Regulation Genes Hospitalization In Situ Hybridization Inflammation Inflammatory Inhalation Interleukin-17 Knowledge Lead Lymphocyte Messenger RNA MicroRNAs Modality New York Pathway interactions Patients Public Health Quality of life Registries Regulation Regulator Genes Role Sampling Severities Severity of illness Sputum Steroid Resistance Systems Biology Therapeutic Toll-Like Receptor Pathway Transfection Universities Untranslated RNA Work airway epithelium airway inflammation airway obstruction asthma exacerbation cohort experimental study extracellular extracellular vesicles improved improved outcome member neutrophil novel response therapeutic development therapeutic target transcriptome sequencing treatment response

项目摘要

Neutrophilic airway inflammation is associated with increased asthma severity. Nearly 50% of patients with asthma are non-eosinophilic and thus less likely to respond completely to corticosteroid therapy or current biologics, illustrating the unmet need to improve our understanding of this group of patients. Despite these associations, the pathways involved in neutrophilic asthma (NA) are only partially understood. MicroRNAs (miRNAs) exert a powerful effect on gene regulation and have been implicated in T helper 2 airway inflammation in asthma. However, there is a knowledge gap in our understanding of the role of miRNAs in NA. MiR-223-3p is associated with severe NA and leads to airway epithelial changes, implicating miRNAs in NA. Work by our group at the Yale Center for Asthma and Airway Disease cohort (YCAAD) found that miR-223-3p belongs to a network of a dozen miRNAs in sputum cells associated with airflow obstruction, asthma hospitalizations, decreased asthma quality of life, lymphocyte and neutrophil counts in the sputum. To understand this cell-specific association we performed in situ hybridization to identify sputum cells expressing miR-223-3p and found that neutrophils express high levels of miR-223-3p. This miRNA is positively correlated with toll-like receptor pathways and IL-17 expression in patients with asthma. We hypothesize that the sputum miRNA network is involved in the regulation of the Th17 pathway and neutrophilic airway inflammation in asthma. We will utilize two well characterized cohorts, YCAAD and the New York University/Bellevue Asthma Registry (NYUBAR), to execute the following aims: Aim 1. To determine the longitudinal expression of the sputum miRNA network and its role in neutrophilic airway inflammation. This aim will determine the stability of miRNA expression in the YCAAD cohort and will validate the expression of the miRNA network in the NYUBAR cohort. Aim 2. To define the network miRNAs released in extracellular vesicles and their association with neutrophilic airway inflammation. This aim will determine the extent to which unique network miRNAs are released into the extracellular environment via extracellular vesicles (EVs) and exert their functional role in the regulation of Th17 inflammation in airway epithelial cells. Aim 3. To determine the effect of the miRNA network in airway epithelial gene expression and its contribution to neutrophilic airway inflammation. This aim will elucidate how the miRNAs in the network interact with each other and how their regulatory role converges on specific inflammatory pathways. These studies will investigate a poorly understood asthma endotype using a novel paradigm of miRNA regulation of neutrophilic airway inflammation. The results derived from this project will lay the foundation for the improved identification of gene regulatory networks involved in NA and lead to potential therapeutic manipulation of miRNAs in neutrophilic airway inflammation.

中性粒细胞性气道炎症与哮喘严重程度增加有关。近50%的患者