Metabolic profiles of COPD phenotypes

描述（由申请人提供）：尽管慢性阻塞性肺疾病（COPD）主要发生在吸烟者中，但尚不清楚为什么只有少数吸烟者（约20-40%）发生慢性气流受限和/或远端气腔破坏（肺气肿）。我们使用代谢组学、基因组学和动物模型的初步工作已经确定鞘脂的失调是COPD和肺气肿发病机制中的关键步骤。神经酰胺等鞘脂的鉴定可作为COPD代谢组学研究的范例。该提案将侧重于使用NHLBI赞助的COPDGene队列来识别候选人，该队列是一个10，000名受试者，患有和不患有COPD的吸烟者的高表型队列。使用这种整合的代谢组学-基因组学-动物模型方法，我们预计我们将确定其他失调的途径，这些途径可以解释为什么一些吸烟者会患COPD和肺气肿，而其他吸烟者则不会。该项目的第一步（目标1）将是确定血浆和支气管肺泡灌洗液中的新代谢途径，这些途径在COPD和肺气肿中失调。然后将使用综合代谢组学和基因组学方法在小鼠中研究候选途径（目标2和3）。将使用途径分析来鉴定在失调代谢组中起作用的酶的候选基因（目的3）。这些酶将作为进一步研究的目标，使用动物模型（目标2）以及通过基因组方法（目标3）。

DESCRIPTION (provided by applicant): Although chronic obstructive pulmonary disease (COPD) occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develop chronic airflow limitation and/or destruction of distal airspaces (emphysema). Our preliminary work using metabolomics, genomics and animal models has identified dysregulation of sphingolipids as a crucial step in the pathogenesis of COPD and emphysema. The identification of spingolipids such as ceramides can serve as a paradigm for metabolome studies of COPD. This proposal will focus on identifying candidates using the NHLBI sponsored COPDGene cohort, which is a 10,000 subject, highly-phenotyped cohort of smokers with and without COPD. Using this integrated metabolomics-genomics-animal model approach, we anticipate that we will identify other dysregulated pathways that can explain why some smokers get COPD and emphysema yet other smokers do not. The first step (Aim 1) of the project will be to identify novel metabolic pathways in plasma and bronchoalveolar lavage fluid that are dysregulated in COPD and emphysema. Candidate pathways will then be investigated in mice using integrated metabolomic and genomic approaches (Aim 2 and 3). Pathway analysis will be used to identify candidate genes for enzymes that play a role in the dysregulated metabolome (Aim 3). These enzymes will be targeted for further study using animal models (Aim 2) as well as through genomic approaches (Aim 3).