COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function

描述(由申请人提供)：在美国，吸烟是慢性阻塞性肺疾病(COPD)的主要原因，是导致死亡的第四大原因。COPD发病机制的核心是“纤毛病变”，这是一种呼吸道纤毛细胞功能障碍，负责调节黏液的运输，以清除吸入的病原体。慢性阻塞性肺疾病的睫毛病变导致粘液堆积、宿主防御功能受损和反复感染。使用全球最先进的代谢物分析平台和独特的血清和肺生物样本队列，我们的成果是识别专注于与COPD气道纤毛病变相关的生物标记物的代谢组，并利用观察到的代谢变化：(1)直接进行机制研究，在分子水平上定义纤毛病变；(2)确定COPD治疗干预的新靶点；以及(3)识别COPD的高风险吸烟者。初步的代谢数据为我们带来了第一条线索--COPD吸烟者血清瓜氨酸水平降低，这与肺一氧化氮合酶(NOS)活性缺乏一致，从而导致肺一氧化氮(NO)缺乏。这一点，再加上吸烟引起的一氧化氮合酶/一氧化氮相关的纤毛病变的支持数据，以及吸烟者在呼吸道上皮转录组中有显著的氧化剂相关变化的知识，导致了我们的目标，将确定队列的代谢组学、小鼠和人类机制研究以及计算/统计整合结合在一起。目的1.对我们特征队列中储存的生物样本进行代谢谱分析，以评估吸烟诱导的COPD与血清和肺ELF中独特的代谢物相关的假说，以及COPD代谢物的亚群与COPD的纤毛病变有关的假设。目的2.结合人和小鼠呼吸道上皮的代谢谱和体外研究，评估COPD代谢组(侧重于推测的NO缺乏)与COPD纤毛病变潜在机制之间存在联系的假说。目的3.对香烟烟雾引起的肺和血清中氧化还原体进行表征和定量，并评价其在纤毛细胞功能障碍中的作用。研究试图确定吸烟、氧化剂对肺上皮细胞的负担与慢性阻塞性肺疾病发病机制之间的联系-可能提供预测哪些吸烟者将患上慢性阻塞性肺疾病的生物标志物(S)，并为慢性阻塞性肺疾病的治疗寻找新的靶点。

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.