COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function

描述（由申请人提供）：吸烟是导致慢性阻塞性肺疾病（COPD）的主要原因，是美国第四大死亡原因。慢性阻塞性肺病发病机制的核心是“纤毛病”，即介导粘液运输以清除吸入病原体的气道纤毛细胞功能障碍。慢性阻塞性肺病纤毛病导致黏液积聚、宿主防御受损和反复感染。利用最先进的全球代谢物分析平台和独特的血清和肺生物样本队列，我们的成果是确定一个代谢组，专注于与COPD气道纤毛病相关的生物标志物，并利用观察到的代谢变化：(1)直接机制研究，在分子水平上定义纤毛病；(2)确定COPD治疗干预的新靶点；(3)识别COPD高危吸烟者。初步的代谢数据为我们提供了第一个线索-慢性阻塞性肺病吸烟者血清瓜氨酸水平降低，与肺一氧化氮合酶（NOS）活性缺乏一致，因此肺一氧化氮（NO）缺乏。这一点，再加上吸烟诱导的NOS/ no相关纤毛病的支持数据，以及吸烟者在气道上皮转录组中具有显着的氧化相关变化的知识，导致了我们的目标，结合已定义队列的代谢组学，小鼠和人类机制研究和计算/统计整合。目的1。对来自我们的特征队列的生物样本进行代谢分析，以评估吸烟诱导的COPD与血清和肺ELF中独特的代谢组相关的假设，以及COPD代谢组亚群与COPD纤毛病相关的假设。目标2。结合人类和小鼠气道上皮的代谢谱和体外研究，评估COPD代谢组（重点关注推断的NO缺乏）与COPD纤毛病机制之间存在联系的假设。目标3。表征和量化香烟烟雾在肺和血清中诱导的“氧化多色体”，并评估其在纤毛细胞功能障碍中的作用。研究试图确定吸烟、肺上皮氧化负担和COPD发病机制之间的联系——可能提供预测哪些吸烟者会发展为COPD的生物标志物，并确定COPD治疗的新靶点。

DESCRIPTION (provided by applicant): With >1014 oxidants/puff, cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), the 4th cause of mortality in the US. Central to COPD pathogenesis is "ciliopathy", dysfunction of the airway ciliated cells that mediate transport of mucus to remove inhaled pathogens. The COPD ciliopathy leads to mucus accumulation, impaired host defense and recurrent infections. Using a state-of-the-art platform for global metabolite profiling and unique cohorts with serum and lung biologic samples, our deliverables are to identify a metabolome focused on biomarkers related to airway ciliopathy in COPD, and use the observed metabolic changes to: (1) direct mechanistic studies to define ciliopathy at a molecular level; (2) identify novel targets for therapeutic intervention in COPD; and (3) identify smokers at high risk for COPD. Preliminary metabolic data led to our first clues - COPD smokers have decreased serum citrulline levels, consistent with a deficiency in lung nitric oxide synthase (NOS) activity, and thus lung nitric oxide (NO) deficiency. This, together with supporting data of a smoking-induced NOS/NO-related ciliopathy, and knowledge that smokers have significant oxidant-related changes in the airway epithelial transcriptome, led to our aims, combining metabolomics of defined cohorts, murine and human mechanistic studies and computational / statistical integration. Aim 1. To carry out metabolic profiling of banked biologic samples from our characterized cohorts to assess the hypothesis that smoking-induced COPD is associated with a unique metabolome in serum and lung ELF, and that subsets of the COPD metabolome are linked to the ciliopathy of COPD. Aim 2. To combine metabolic profiling and in vitro studies of human and murine airway epithelium to evaluate the hypothesis that there is a link between the COPD metabolome (focusing on the inferred NO deficiency) and mechanisms underlying the ciliopathy of COPD. Aim 3. Characterize and quantify the cigarette smoke induced "redoxome" in lung and serum and assess its role in ciliated cell dysfunction. Studies seek to identify a link between smoking, burden of oxidants to the lung epithelium and the pathogenesis of COPD - potentially providing biomarker(s) that predict which smokers will develop COPD and identifying new targets for therapy of COPD.