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.

项目摘要 非型助手2（TH2，也在2型）哮喘内型尚不理解 对现有哮喘治疗剂的反应有限。对于患者而言，这种需求尤其明显 由于疾病的严重疾病以及对这些内型病理生物学的理解是紧迫的。与 对K01指导的支持，我们已经确定了与中性粒细胞相关的microRNA网络 哮喘，非T2哮喘内型。基于microRNA在基因调节中扮演的重要作用 正常组织和疾病，我们正在追求新的假设，即miR-223-3p是必不可少的生物标志物 和中性粒细胞气道炎症的调节剂。 miR-223-3p与严重的嗜中性哮喘有关，我们的初步研究发现了阳性 其表达与痰液中Th17炎症之间的相关性。鉴于 Th17炎症在通过IL-17分泌的嗜中性哮喘发育和维持中的已知作用。 我们假设miR-223-3p参与了TH17途径和中性粒细胞气道的调节 哮喘发炎。我们将在耶鲁大学哮喘和气道疾病中心使用痰液样品 （YCAAD）队列和体外模型，以执行以下目的： 目的1。确定miR-223-3p的表达，Th17细胞因子及其与中性粒细胞的缔合 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 在YCAAD的患者痰中。 目标2。确定miR-223-3p在气道上皮的转录组和分泌蛋白质组中的影响 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。在AIM中收集的患者样品中，将鉴定丰富的分泌蛋白质 1。 这些研究将研究miR-223-3p如何通过哮喘中嗜中性气道炎症做出贡献 通过Th17途径调节以及我们如何使用混合生物标志物，由组合产生 miR-223-3p表达和Th17细胞因子，以将这种独特的哮喘内型分类。 从该项目得出的结果将为改善患者的鉴定奠定基础 严重的嗜中性哮喘，并更好地了解miR-223-3p如何调节中性粒细胞气道 炎。