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: 10434046
• 负责人: Jose Luis Gomez-Villalobos
• 金额: $ 62.85万
• 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/10434046
• 关键词: Address; Adrenal Cortex Hormones; Affect; Airway Disease; Asthma; Biological; Biological Products; 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; 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; gene regulatory network; improved; improved outcome; member; miRNA expression profiling; neutrophil; novel; response; therapeutic development; therapeutic target; transcriptome sequencing; treatment response

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.

嗜中性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的，因此对皮质类固醇治疗或电流完全反应的可能性较小 生物制剂说明了提高我们对这组患者的理解的未满足需要。尽管如此 相关性，仅部分理解了嗜中性哮喘（NA）所涉及的途径。 microRNA （miRNA）对基因调节产生强大的影响，并与T助手2气道炎症有关 在哮喘中。但是，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，这意味着NA中的miRNA。 我们小组在耶鲁大学哮喘和气道疾病队列中心（YCAAD）的工作发现miR-223-3p 属于与气流阻塞，哮喘相关的痰细胞中十几个miRNA网络 痰中的住院治疗，降低哮喘的生活质量，淋巴细胞和中性粒细胞。到 了解我们进行原位杂交的这种细胞特异性关联，以鉴定表达的痰细胞 miR-223-3p，发现中性粒细胞表达高水平的miR-223-3p。这个miRNA是正相关的 哮喘患者的TOLL样受体途径和IL-17的表达。 我们假设痰miRNA网络参与了TH17途径的调节和 哮喘中嗜中性气道炎症。我们将利用两个特征良好的队列，YCAAD和新的 约克大学/贝尔维尤哮喘注册表（Nyubar）执行以下目标： 目标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。这个目的将确定miRNA表达在YCAAD队列中的稳定性，并将 验证miRNA网络在Nyubar队列中的表达。 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。这个目标将确定独特网络miRNA被释放到多大程度上 细胞外环境通过细胞外囊泡（EV），并在TH17的调节中发挥其功能作用 气道上皮细胞中的炎症。 目标3。确定miRNA网络在气道上皮基因表达及其贡献中的影响 嗜中性气道炎症。这个目标将阐明网络中的miRNA如何与每个网络相互作用 其他以及他们的调节作用如何在特定的炎症途径上融合。 这些研究将使用新型miRNA范式研究尚未了解的哮喘内型 调节中性粒细胞气道炎症。从该项目得出的结果将为 改善了涉及NA的基因调节网络并导致潜在的治疗操作的鉴定 中性粒细胞气道炎症中的miRNA。