Regulation of Neutrophilic Airway Inflammation by miR-223-3p

miR-223-3p 对中性粒细胞气道炎症的调节

• 批准号: 10064359
• 负责人: Jose Luis Gomez-Villalobos
• 金额: $ 8.38万
• 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: 2020-07-21 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064359
• 关键词: Address; Adrenal Cortex Hormones; Airway Disease; Asthma; Award; Biological; Biological Markers; Cells; Classification; Custom; Detection; Development; Disease; Epithelial Cells; Foundations; Future; Gene Expression Regulation; Hospitalization; Hybrids; In Situ Hybridization; Inflammation; Inhalation; Interleukin-17; Knowledge; Lead; Lymphocyte; Maintenance; Measures; Mentors; Messenger RNA; MicroRNAs; Modeling; Normal tissue morphology; Nucleotides; Pathogenesis; Pathway interactions; Patients; Play; Protein Array; Protein Secretion; Proteins; Proteome; Public Health; Quality of life; Regulation; Role; Sampling; Severities; Severity of illness; Sputum; Steroid Resistance; Testing; Therapeutic; Toll-Like Receptor Pathway; Untranslated RNA; Work; airway epithelium; airway inflammation; airway obstruction; asthma exacerbation; base; cohort; cytokine; experimental study; improved; improved outcome; in vitro Model; mRNA Expression; neutrophil; novel; novel marker; overexpression; patient subsets; response; therapeutic target; transcriptome; transcriptome sequencing; treatment response

PROJECT SUMMARY Non-Type helper 2 (Th2, also known at type 2) asthma endotypes are poorly understood despite their association with limited response to existing asthma therapeutics. This need is particularly evident for patients with severe disease, and improved understanding of the pathobiology of these endotypes is urgent. With the support of a K01 mentored-award, we have identified a network of microRNAs associated with neutrophilic asthma, a non-T2 asthma endotype. Based on the essential role played by microRNAs in gene regulation on normal tissues and disease, we are pursuing the novel hypothesis that miR-223-3p is an essential biomarker and regulator of neutrophilic airway inflammation. MiR-223-3p is associated with severe neutrophilic asthma, and our preliminary studies have found a positive correlation between its expression and Th17 inflammation in the sputum. This finding is significant given the known role of Th17 inflammation in the development and maintenance of neutrophilic asthma via IL-17 secretion. We hypothesize that miR-223-3p is involved in the regulation of the Th17 pathway and neutrophilic airway inflammation in asthma. We will utilize sputum samples in the Yale Center for Asthma and Airway Disease (YCAAD) cohort, and in vitro models, to execute the following aims: Aim 1. To determine the expression of the miR-223-3p, Th17 cytokines, and their association with neutrophilic airway inflammation. This aim will determine the association between miR-223-3p and Th17 pathway cytokines in the sputum of patients at YCAAD. Aim 2. To determine the effect of miR-223-3p in the transcriptome and secretory proteome of airway epithelial cells. This aim will determine the regulatory effects of miR-223-3p on the airway transcriptome and secretory proteome. The identification of abundant secreted proteins will be validated in patient samples collected in Aim 1. These studies will investigate how miR-223-3p contributes through neutrophilic airway inflammation in asthma via Th17 pathway regulation and how we can potentially use a hybrid biomarker, resulting from the combination of miR-223-3p expression and Th17 cytokines, to classify patients with this distinct asthma endotype. The results derived from this project will lay the foundation for the improved identification of patients with severe neutrophilic asthma and lead to a better understanding of how miR-223-3p regulates neutrophilic airway inflammation.

项目概要 尽管非辅助型 2 型（Th2，也称为 2 型）哮喘内型的了解很少，但 与现有哮喘治疗反应有限有关。这种需求对于患者来说尤为明显 患有严重疾病，迫切需要提高对这些内型病理学的了解。随着 在 K01 指导奖的支持下，我们已经确定了与中性粒细胞相关的 microRNA 网络 哮喘，一种非 T2 哮喘内型。基于 microRNA 在基因调控中发挥的重要作用 正常组织和疾病，我们正在追求 miR-223-3p 是一种重要生物标志物的新假设 和中性粒细胞气道炎症的调节剂。 MiR-223-3p 与严重中性粒细胞性哮喘相关，我们的初步研究发现了积极的作用 其表达与痰中Th17炎症的相关性。鉴于 已知 Th17 炎症通过 IL-17 分泌在中性粒细胞性哮喘的发生和维持中的作用。 我们假设 miR-223-3p 参与 Th17 通路和中性粒细胞气道的调节 哮喘中的炎症。我们将利用耶鲁大学哮喘和气道疾病中心的痰样本 (YCAAD) 队列和体外模型，以实现以下目标： 目的 1. 确定 miR-223-3p、Th17 细胞因子的表达及其与中性粒细胞的关系 气道炎症。该目标将确定 miR-223-3p 和 Th17 途径细胞因子之间的关联 YCAAD 患者的痰液中。 目的2.确定miR-223-3p对气道上皮转录组和分泌蛋白质组的影响 细胞。该目标将确定 miR-223-3p 对气道转录组和分泌的调节作用 蛋白质组。丰富的分泌蛋白的鉴定将在 Aim 收集的患者样本中得到验证 1. 这些研究将调查 miR-223-3p 如何通过哮喘中性粒细胞气道炎症发挥作用 通过 Th17 通路调节以及我们如何可能使用由组合产生的混合生物标志物 miR-223-3p 表达和 Th17 细胞因子，对具有这种独特哮喘内型的患者进行分类。 该项目的结果将为改善患者识别奠定基础 严重中性粒细胞性哮喘，并有助于更好地了解 miR-223-3p 如何调节中性粒细胞气道 炎。