Metabolome and proteome profiles of emphysema and airway disease

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是世界上最常见的肺部疾病，但很少有人知道为什么只有20%的吸烟者容易患上这种疾病。COPD通常作为单一疾病进行研究，传统上使用肺量测定法进行诊断;然而，最近的研究表明，COPD更可能是一种具有多种吸烟相关表型的异质性综合征。两种最常见的表型包括肺气肿和气道疾病;这些表型与肺量测定法的相关性很差，并且具有独立于肺量测定法的临床意义。在我们的初步数据中，我们已经确定了肺气肿和气道疾病的不同分子特征，这表明可能存在决定吸烟者临床表型类型的分子基础。本提案的目标是（1）使用蛋白质组学和代谢组学方法来鉴定与COPD表型相关的新血浆生物标志物，以及（2）鉴定这些生物标志物的遗传控制。这一提议极具成本效益，因为受试者招募、全基因组分析和高分辨率CT（HRCT）扫描已经通过COPDGene获得。通过该提案获得的知识包括开发COPD表型的快速血液检测，提高对不同COPD表型的分子基础的理解，以及对代谢和血浆蛋白表达的遗传控制的新理解。公共卫生相关性：慢性阻塞性肺疾病（COPD）是美国第四大常见死因，到2020年将成为第三大常见死因。吸烟是COPD最常见的原因;然而，大多数吸烟的人不会患上COPD。肺气肿是一种“COPD的表型”，并且由肺组织的弹性丧失（增加的顺应性）、由支持肺泡的结构的破坏和供给肺泡的毛细血管的破坏引起。肺气肿最好使用高分辨率CT扫描检测。该提案旨在发现与肺气肿相关的生物标志物，以确定更多关于香烟烟雾如何导致COPD的信息，并开发更好的血液测试以确定吸烟者患上这种疾病的风险。这项研究还将研究基因如何控制血液中的蛋白质表达，从而增加我们对遗传背景如何决定一个人对香烟烟雾的反应的理解。(End摘要）

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the most common lung disease in the world, yet little is known about why only 20% of smokers are susceptible to developing the disease. COPD is usually studied as a single disease and traditionally diagnosed using spirometry; however, recent work suggests that COPD is more likely a heterogeneous syndrome with multiple smoking-related phenotypes. Two of the most common phenotypes include emphysema and airway disease; these phenotypes are poorly correlated with spirometry and have clinical implications independent of spirometry. In our preliminary data we have identified distinct molecular signatures for emphysema and airway disease suggesting that there may be a molecular basis that determines the type(s) of clinical phenotypes that develop in smokers. The goals of this proposal are to (1) use proteomic and metabolomic approaches to identify new plasma biomarkers that are associated with COPD phenotypes and (2) identify the genetic control of these biomarkers. This proposal is extremely cost effective because subject recruitment, whole genome analysis and high resolution CT (HRCT) scans are already being obtained through COPDGene. Knowledge gained by this proposal includes development of rapid blood tests for COPD phenotypes, an improved understanding of the molecular basis of different COPD phenotypes, and a new understanding of the genetic control of metabolism and plasma protein expression. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the United States and will be the third most common cause of death by 2020. Cigarette smoke is the most common cause of COPD; yet, most people who smoke do not develop COPD. Emphysema is one "phenotype of COPD" and is caused by loss of elasticity (increased compliance) of the lung tissue, from destruction of structures supporting the alveoli, and destruction of capillaries feeding the alveoli. Emphysema is best detected using a high resolution CT scan. This proposal aims to discover biomarkers that are associated with emphysema in order to determine more about how cigarette smoke causes COPD and to develop a better blood test to determine risk of developing the disease in smokers. The study will also study how genes control protein expression in the blood, thereby increasing our understanding on how genetic background determines a person's response to cigarette smoke. (End of Abstract)