COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function

描述（由申请人提供）：在>1014氧化剂/喷烟的情况下，吸烟是慢性阻塞性肺病（COPD）的主要原因，COPD是美国第四大死亡原因。COPD发病机制的中心是“纤毛病”，即介导粘液运输以去除吸入病原体的气道纤毛细胞的功能障碍。COPD纤毛病变导致粘液积聚、宿主防御受损和复发性感染。使用最先进的全球代谢物谱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，重点是与COPD气道纤毛病变相关的生物标志物，并使用观察到的代谢变化：（1）指导机制研究，以在分子水平上定义纤毛病变;（2）确定COPD治疗干预的新靶点;（3）确定COPD治疗干预的新靶点。（3）识别COPD高危吸烟者。初步代谢数据为我们提供了初步线索- COPD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。这与吸烟诱导的NOS/NO相关纤毛病变的支持数据以及吸烟者在气道上皮转录组中具有显著氧化剂相关变化的知识一起导致了我们的目标，结合了定义队列的代谢组学，小鼠和人类机制研究以及计算/统计整合。目标1.对来自我们特征化队列的库存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中的独特代谢组相关以及COPD代谢组亚组与COPD纤毛病变相关的假设。目标二。结合联合收割机代谢谱和人和小鼠气道上皮细胞的体外研究，以评估COPD代谢组（侧重于推断的NO缺乏）与COPD纤毛病变潜在机制之间存在联系的假设。目标3：表征和量化香烟烟雾诱导的肺和血清中的“氧化还原体”，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、肺上皮的氧化剂负荷和COPD发病机制之间的联系-潜在地提供预测哪些吸烟者将发展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.