Identification of immune cell-cell communication networks and inflammatory pulmonary microenvironments associated with the progression of COPD

项目总结 慢性阻塞性肺疾病(COPD)是一种致命的肺部疾病，是第四大致死原因 在美国，尽管每年的医疗费用估计有500亿美元，但目前还没有治愈方法，只有缓解- Ive治疗。慢性阻塞性肺疾病的明显特征是慢性肺部炎症，可能是由于调节失调引起的。 免疫因子和细胞的复杂网络跨多个组织隔间的离子。尽管有多个 单个基因和蛋白质与COPD的风险和进展有关，全球机制 对其病理生理学缺乏了解，特别是对于COPD的显著异质性。 表型。我们研究的总体目标是在系统水平上深入了解复杂的炎症性和 通过应用数据驱动(也称为机器学习)建模，研究COPD背后的免疫机制 从人体肺微环境和配对免疫细胞中采集临床标本的方法 来自外周血液的网络。我们的中心假设是，免疫网络将更好地预测 COPD的表型、进展、恶化比个体因素多。我们将在三个月内检验这一假说 特定目标，使用SPIROMICS I和SPIROMICS I和SPIROMICS I收集的匹配的支气管肺泡灌洗(BAL)和血液样本 II临床试验。目标1将通过高吞吐量识别免疫细胞-细胞通信网络的变化 吸烟者外周血免疫细胞刺激系统中细胞因子的测定 没有COPD和不吸烟控制(从即将到来的SPIROMICS II访问中收集；n=150)。目标2 将使用高通量确定在发炎的肺微环境中发生的系统级变化 BAL样本中细胞因子的测定(均来自SPIROMICS I，n=200，收集于 即将到来的SPIROMICS II支气管镜检查)，来自患有和不患有COPD的吸烟者和从不吸烟的对照组。 我们将确定与纵向临床进展和恶化频率相关的网络。目标3 将整合肺和血液组织隔间的测量，以定义关键的组合 与进展和恶化事件相关的关系。总体而言，该项目将提供以下系统- 深入了解COPD的发病机制和进展，为其他疾病的研究创造新的范式 涉及慢性炎症的肺部疾病，包括特发性肺纤维化、哮喘和肺 移植。结果将有助于未来新的非侵入性诊断分析的发展，并将指导 系统水平的机制研究，可能导致新的组合疗法。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a fatal lung disease that is the fourth leading cause of death in the U.S. Despite an estimated $50 billion in yearly healthcare costs, it has no current cure and only palliat- ive treatments. COPD is clearly characterized by chronic lung inflammation that likely arises from dysregulat- ion of complex networks of immune factors and cells across multiple tissue compartments. Although multiple individual genes and proteins have been associated with COPD risk and progression, global mechanistic understanding of its pathophysiology is lacking, particularly regarding the marked heterogeneity in COPD phenotypes. The overall objective of our study is to gain systems-level insight into complex inflammatory and immune mechanisms underlying COPD, by applying data-driven (also called ‘machine learning’) modeling approaches to clinical samples collected from human pulmonary microenvironments and matched immune cell networks from peripheral blood. Our central hypothesis is that immune networks will be more predictive of COPD phenotype, progression, and exacerbation than individual factors. We will test this hypothesis in three Specific Aims, using matched brochoalveolar lavage (BAL) and blood samples collected in SPIROMICS I and II clinical trials. Aim 1 will identify changes in immune cell-cell communication networks, by high-throughput cytokine measurements from stimulated systems of peripheral blood immune cells from smokers with and without COPD and never-smoking controls (collected from the upcoming SPIROMICS II visit; n=150). Aim 2 will determine systems-level changes that occur in the inflamed lung microenvironment, using high-throughput cytokine measurements in BAL samples (both archival from SPIROMICS I, n=200, and collected during upcoming SPIROMICS II bronchoscopies) from smokers with and without COPD and never-smoking controls. We will identify networks associated with longitudinal clinical progression and exacerbation frequency. Aim 3 will integrate measurements across lung and blood tissue compartments to define key combinatorial relationships associated with progression and exacerbation events. Overall, this project will provide systems- level insight into COPD pathogenesis and progression, and create a new paradigm for the study of other pulmonary conditions involving chronic inflammation, including idiopathic pulmonary fibrosis, asthma, and lung transplant. Results will aid in the future development of new non-invasive diagnostic assays and will guide systems-level mechanistic studies that could result in new combinatorial therapies.