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

• 批准号: 10599639
• 负责人: Jose Luis Gomez-Villalobos
• 金额: $ 12.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10599639
• 关键词: Adrenal Cortex Hormones; Airway Disease; Asthma; Biological; Biological Products; Cells; Environment; Epithelial Cells; Foundations; Gene Expression; Gene Expression Regulation; Hospitalization; In Situ Hybridization; Inflammation; Inflammatory; Interleukin-17; Knowledge; Lead; Lymphocyte; MicroRNAs; Modality; New York; Pathway interactions; Patients; Public Health; Quality of life; Registries; Regulation; Role; Severities; Severity of illness; Sputum; Systems Biology; Therapeutic; Toll-Like Receptor Pathway; Universities; Work; airway epithelium; airway inflammation; airway obstruction; asthma exacerbation; cohort; extracellular; extracellular vesicles; gene regulatory network; improved; improved outcome; neutrophil; novel; parent grant; response; therapeutic development

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.

中性粒细胞气道炎症与哮喘严重程度增加有关。近50%的患者 哮喘是非嗜酸性粒细胞性的，因此不太可能对皮质类固醇治疗或目前的治疗完全反应 生物制剂，说明了提高我们对这组患者的了解的未满足的需求。尽管有这些 尽管中性粒细胞性哮喘 (NA) 相关的通路尚不完全清楚。微小RNA (miRNA) 对基因调控发挥强大作用，并与 T 辅助细胞 2 气道炎症有关 在哮喘中。然而，我们对 miRNA 在 NA 中的作用的理解存在知识差距。 MiR-223-3p 与严重的 NA 相关，并导致气道上皮变化，表明 NA 中存在 miRNA。 我们耶鲁大学哮喘和气道疾病中心 (YCAAD) 团队的工作发现，miR-223-3p 属于痰细胞中与气流阻塞、哮喘相关的十几个 miRNA 网络 住院治疗、哮喘生活质量下降、痰中淋巴细胞和中性粒细胞计数下降。到 为了了解这种细胞特异性关联，我们进行了原位杂交来识别表达痰细胞 miR-223-3p，发现中性粒细胞表达高水平的 miR-223-3p。该 miRNA 呈正相关 哮喘患者中 Toll 样受体途径和 IL-17 表达的关系。 我们假设痰 miRNA 网络参与 Th17 通路的调节 哮喘中性粒细胞性气道炎症。我们将利用两个特征明确的队列：YCAAD 和 New 约克大学/贝尔维尤哮喘登记处 (NYUBAR)，以实现以下目标： 目的 1. 确定痰 miRNA 网络的纵向表达及其在中性粒细胞中的作用 气道炎症。这一目标将确定 YCAAD 队列中 miRNA 表达的稳定性，并将 验证 NYUBAR 队列中 miRNA 网络的表达。 目标 2. 定义细胞外囊泡中释放的网络 miRNA 及其与中性粒细胞的关联 气道炎症。这个目标将决定独特的网络 miRNA 被释放到网络中的程度。 通过细胞外囊泡 (EV) 调节细胞外环境并发挥其在 Th17 调节中的功能作用 气道上皮细胞炎症。 目标 3. 确定 miRNA 网络在气道上皮基因表达中的作用及其贡献 至中性粒细胞性气道炎症。这一目标将阐明网络中的 miRNA 如何与每个 miRNA 相互作用 其他以及它们的调节作用如何集中于特定的炎症途径。 这些研究将使用一种新的 miRNA 范式来研究人们知之甚少的哮喘内型 中性粒细胞气道炎症的调节。该项目的成果将为 改进对 NA 涉及的基因调控网络的识别并导致潜在的治疗操作 中性粒细胞气道炎症中的 miRNA。