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: 10221048
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221048
• 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.

项目总结 非2型辅助细胞(Th2，也称为2型)哮喘内型知之甚少 与现有哮喘治疗药物反应有限有关。这一需求对患者来说尤其明显。 严重的疾病，以及对这些内型的病理生物学的更好的理解是迫切的。与 在K01导师奖的支持下，我们发现了一个与中性粒细胞相关的microRNAs网络 哮喘，一种非T2哮喘内型。基于microRNAs在基因调控中的重要作用 对于正常组织和疾病，我们正在追寻一种新的假设，即miR-223-3p是一个重要的生物标志物 和中性粒细胞呼吸道炎症的调节剂。 MiR-223-3p与严重的中性粒细胞哮喘有关，我们的初步研究发现 其表达与痰中Th17炎症的相关性研究这一发现具有重要意义，因为 已知Th17炎症通过分泌IL-17在中性粒细胞哮喘的发生和维持中的作用。 我们推测miR-223-3p参与了Th17途径和中性粒细胞的调节。 哮喘中的炎症。我们将利用耶鲁哮喘和呼吸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.检测mIR-223-3p、Th17细胞因子的表达及其与中性粒细胞的关系 呼吸道发炎。这一目标将确定miR-223-3p和Th17途径细胞因子之间的关联 在YCAAD的病人的痰中。 目的：研究miR-223-3p对呼吸道上皮细胞转录和分泌蛋白质组的影响。 细胞。这一目标将决定miR-223-3p对呼吸道转录和分泌的调节作用。 蛋白质组。大量分泌蛋白的鉴定将在AIM收集的患者样本中得到验证。 1. 这些研究将探讨miR-223-3p如何通过中性粒细胞炎症在哮喘中发挥作用。 通过Th17途径调节，以及我们如何潜在地使用组合产生的混合生物标记物 MiR-223-3p的表达和Th17细胞因子的表达，以对这种独特的哮喘内型患者进行分类。 这一项目的结果将为改进对患者的识别奠定基础 更好地了解miR-223-3p如何调节中性粒细胞哮喘 发炎。