Transcriptomic signatures of airway inflammation in acute respiratory diseases

项目总结/摘要：炎症失调是急性呼吸道疾病的有力驱动因素 病理学，包括慢性阻塞性肺疾病急性加重（AECOPD）和急性 呼吸窘迫综合征（ARDS），这两种疾病的发病率，死亡率和 医疗费用。这些病症是通过临床和生理标准诊断的，包括患有以下疾病的患者： 异质性免疫生物学，这导致疗效有限的不精确治疗。存在一个临界 需要了解肺部的异质性炎症失调，以开发精确的诊断方法 以及这些综合征的治疗方法。这个建议建立在我的导师之前的工作基础上， 区分具有相似基础生物学的患者亚组的炎性生物标志物，或“分子生物标志物”， 在ARDS和COPD中的“表型”。我的共同导师，克里斯滕森博士，确定了两种分子表型， 以增强的2型（T2）或2型（T2）气道基因组特征增加为特征的稳定型COPD 17（T17）炎症。这些亚组表现出明显的临床差异，包括对治疗的反应 类固醇。我的初步数据表明，我们可以扩展极化免疫的分子表型， 对AECOPD患者的反应。我的主要导师，卡尔菲博士，确定了高度炎症和 基于临床数据和血浆蛋白生物标志物的ARDS低炎性分子表型。的 表型与死亡率和对治疗反应的差异相关。的差异 这些分子表型之间的肺部炎症尚不清楚。转录组学分析 从这些患者的呼吸道中提取的样本可以鉴定特异性免疫途径在这些疾病中的作用。 导致这种不同的高度炎症和低炎症分子表型的病理生理学。 这项建议的总体目标是研究呼吸道炎症的基因组标志物在 通过使用先前的转录组学数据区分AECOPD和ARDS分子表型 在表型良好的队列中对气道样本进行测序。在目标1中，我们将使用痰液测序和临床 来自COPD患者队列的数据，以检测AECOPD分子表型的存在。我 假设AECOPD有多种分子表型， 急性加重期间T1、T2或T17炎症的预定义基因特征。我进一步假设， 稳定期COPD患者的这些相同特征将是对以下疾病易感性的预后生物标志物： 这些途径被富集的恶化。在目标2中，我将测试分子的存在， 使用来自观察性队列的气管抽吸物的RNA测序数据对ARDS表型进行分析。我 假设呼吸道转录反应将提供对炎症在呼吸道炎症中的作用的了解， 肺在先前描述的ARDS发病机制中的分子表型通过血浆鉴定 proteins.

PROJECT SUMMARY/ABSTRACT: Dysregulated inflammation is a potent driver of acute respiratory pathology, including acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and the acute respiratory distress syndrome (ARDS), two conditions with a heavy burden of morbidity, mortality, and healthcare costs. These conditions are diagnosed by clinical and physiologic criteria that include patients with heterogenous immune biology, which has resulted in imprecise therapy with limited efficacy. There is a critical need to understand the heterogeneous inflammatory dysregulation in the lung to develop precision diagnostics and therapies for these syndromes. This proposal builds on prior work by my mentors that identified specific inflammatory biomarkers that distinguish subgroups of patients with similar underlying biology, or “molecular phenotypes” in ARDS and COPD. My co-mentor, Dr. Christenson, identified two molecular phenotypes in stable COPD distinguished by increases in airway genomic signatures of either enhanced Type 2 (T2) or Type 17 (T17) inflammation. These subgroups exhibit distinct clinical differences, including response to treatment with steroids. My preliminary data suggest we can extend molecular phenotypes of polarized immune responses to patients with AECOPD. My primary mentor, Dr. Calfee, identified hyperinflammatory and hypoinflammatory molecular phenotypes in ARDS based on clinical data and plasma protein biomarkers. The phenotypes were associated with differences in mortality and response to treatments. The differences in inflammation in the lung between these molecular phenotypes is not known. Transcriptomic analysis of samples from the respiratory tract in these patients can identify the role of specific immune pathways in the pathophysiology that leads to such distinct hyperinflammatory and hypoinflammatory molecular phenotypes. The overall objective of this proposal is to examine the role of genomic markers of respiratory inflammation in distinguishing AECOPD and ARDS molecular phenotypes by using transcriptomic data from previously sequenced airway samples in well-phenotyped cohorts. In Aim 1, we will use sputum sequencing and clinical data from a cohort of patients with COPD to test for the presence of molecular phenotypes of AECOPD. I hypothesize there are of molecular phenotypes of AECOPD that are distinguished by expression of predefined gene signatures of T1, T2, or T17 inflammation during exacerbations. I further hypothesize that these same signatures in patients with stable COPD will be prognostic biomarkers for susceptibility to exacerbations in which these pathways are enriched. In Aim 2, I will test for the presence of molecular phenotypes of ARDS in using RNA sequencing data from tracheal aspirates from an observational cohort. I hypothesize respiratory tract transcriptional responses will provide insight into the role of the inflammation in the lung in the pathogenesis of previously described ARDS molecular phenotypes identified by plasma proteins.