Lung Microbiome and Inflammation in Early COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）将很快成为世界上第三大死亡原因。COPD是由多种因素引起的，包括环境暴露、感染、炎症和遗传易感性。多项研究表明，在晚期疾病中，细菌定植增加导致气道炎症和加速气道阻塞。然而，在早期COPD中，依赖培养的技术通常无法分离细菌。因此，微生物在COPD中的作用一直难以研究。我们假设微生物是早期COPD发病机制的一部分，有助于炎症过程。该提案将使用非培养技术来评估微生物组对早期COPD气道炎症的贡献。它还将研究微生物基因组潜力（宏基因组）和代谢谱（代谢组），以更好地了解肺微生物组的功能方面。目的1将评估患有和不患有COPD的吸烟者的肺部微生物组和炎症。我们将对48名轻中度COPD受试者和48名匹配的吸烟者对照进行研究性支气管镜检查，通过16S rRNA基因测序对支气管肺泡灌洗液和下气道细菌进行多重细胞因子测定，以测量肺部炎症。目的2将使用AIM 1中获得的样本，使用宏基因组学和代谢组学研究下呼吸道中的活性细菌代谢途径。我们将测试下呼吸道微生物组的基因组潜力差异是否会导致肺代谢组的变化。编码合成途径的操纵子与这些途径的代谢产物之间的相关性的存在将支持肺微生物组是代谢活性的，因此由活微生物组成。目标3将评估COPD和对照组中不同组间数据集（微生物组、宏基因组、代谢组和宿主免疫反应）之间的关系，目的是整合来自不同平台的信息，以实现疾病的多维模型。在Blaser，Weiden博士的指导下，并与Virgin，Fiehn和Clemente博士合作，该研究计划将作为培训计划的基础，该计划使用最先进的分子和生物信息学方法来提高我们对复杂细菌群落网络及其与COPD中宿主免疫反应的关联的理解。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) will soon become the third leading cause of death in the world. COPD is caused by multiple factors including environmental exposures, infections, inflammation, and genetic predisposition. Several lines of investigation have indicated that, in advanced disease, increased bacterial colonization leads to airway inflammation and accelerated airway obstruction. However, in early COPD, culture-dependent techniques commonly failed to isolate bacteria. Thus, the role of microbes in COPD has been difficult to study. We hypothesize that microbes are part of the pathogenesis of early COPD, contributing to inflammatory processes. This proposal will use culture independent techniques to evaluate the contribution of the microbiome to airway inflammation in early COPD. It will also investigate the microbial genomic potential (metagenome) and metabolic profile (metabolome) to better understand functional aspects of the lung microbiome. Aim 1 will assess lung microbiome and inflammation in smokers with and without COPD. We will perform research bronchoscopy in 48 subjects with mild-moderate COPD and 48 matched smoker controls to measure lung inflammation with multiplexed cytokine assays of bronchoalveolar lavage and lower airway bacteria by 16S rRNA gene sequencing. Aim 2 will investigate active bacterial metabolic pathways in the lower airways using metagenomics and metabolomics by using the samples obtained in AIM 1. We will test whether differences in genomic potential of the lower airway microbiome accounts for variation in the lung metabolome. Presence of correlation between operons encoding synthetic pathways and the metabolic products of those pathways would support that the lung microbiome is metabolically active, thus composed by live microorganisms. Aim 3 will assess relationships among different inter-omic datasets (microbiome, metagenome, metabolome and host immune responses) in COPD and controls with the goal of integrating information from vastly different platforms to achieve a multidimensional model of disease. Under the mentorship of Drs. Blaser, Weiden and with the collaboration of Dr. Virgin, Fiehn, and Clemente this research plan will serve as the foundation of a training plan that uses state-of-the-art molecular and bio-informatic methods to improve our understanding of complex bacterial community networks and their association with host immune response in COPD.