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

项目摘要 非辅助型2（Th 2，也称为2型）哮喘内型的了解很少，尽管它们具有 与对现有哮喘治疗剂反应有限相关。这种需求对于患者来说尤为明显 与严重的疾病，并提高这些内型的病理生物学的理解是迫切的。与 在K 01的支持下，我们发现了一个与嗜酸性粒细胞相关的microRNA网络， 哮喘，一种非T2哮喘内型。基于microRNA在基因调控中的重要作用， 正常组织和疾病，我们正在追求新的假设，即miR-223- 3 p是一个重要的生物标志物 和嗜酸性气道炎症的调节剂。 MiR-223- 3 p与严重的嗜酸性哮喘相关，我们的初步研究发现， 其表达与痰液中Th 17炎症的相关性。这一发现意义重大，因为 Th 17炎症通过IL-17分泌在嗜肺性哮喘的发展和维持中的已知作用。 我们假设miR-223- 3 p参与调节Th 17通路和嗜酸性气道 哮喘中的炎症我们将利用耶鲁哮喘和气道疾病中心的痰液样本 （YCAAD）队列和体外模型，以实现以下目标： 目标1.为了确定miR-223- 3 p、Th 17细胞因子的表达，以及它们与嗜酸性粒细胞的相关性， 气道炎症这一目的将确定miR-223- 3 p和Th 17途径细胞因子之间的关联 在YCAAD的病人的痰中发现的 目标二。确定miR-223- 3 p在气道上皮细胞转录组和分泌蛋白质组中的作用， 细胞该目的将确定miR-223- 3 p对气道转录组和分泌的调节作用。 蛋白质组将在Aim采集的患者样本中验证大量分泌蛋白的鉴定 1. 这些研究将探讨miR-223- 3 p如何通过哮喘中的嗜酸性气道炎症发挥作用 通过Th 17途径调节，以及我们如何潜在地使用混合生物标志物， 的miR-223- 3 p表达和Th 17细胞因子，以分类具有这种独特的哮喘内源型的患者。 该项目的结果将为改善患者的识别奠定基础。 严重嗜肺性哮喘，并导致更好地了解miR-223- 3 p如何调节嗜肺性气道 炎症

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.