COPD Susceptibility, Heterogeneity, and Progression: Proteomics and Genetics

项目摘要/摘要 目前慢性阻塞性肺疾病(COPD)的治疗选择有限，新药 由于缺乏临床相关的生物标记物来评估可能的药物，慢性阻塞性肺疾病的发展受到了阻碍 功效。我们将在肺组织中鉴定COPD的差异丰富和肺特异的蛋白质生物标记物 和血液(血浆)使用全面的蛋白质组学分析。影响慢性阻塞性肺疾病的基因决定因素 易感性，但之前发现的COPD基因决定因素只占一小部分 慢性阻塞性肺疾病的遗传性。蛋白质生物标记物的遗传分析可以揭示调控因素的网络 影响COPD易感性和COPD异质性。我们的总体假设是功能性遗传 突变导致蛋白质组状态异常，从而影响COPD的发展和异质性。我们 将通过研究肺组织和血浆中不同的肺特定蛋白来识别潜在的COPD生物标记物 来自100例慢性阻塞性肺疾病患者和50例吸烟控制者。然后我们将测量最有希望的肺- 1950名非西班牙裔白人和非洲裔美国人COPD基因受试者的特异性血浆蛋白 影像特征(以呼吸道为主的COPD、以肺气肿为主的COPD和抵抗型吸烟者) 确定与COPD和COPD亚型相关的蛋白质生物标志物。我们还将表演遗传基因 利用COPD基因全基因组测序数据分析肺特异蛋白水平的相关性 研究对象。蛋白质生物标记物水平的遗传决定因素将被测试与COPD的关联 多个COPD人群的易感性和COPD亚型。然后我们将确定是否 对已确定的COPD易感性的蛋白质生物标志物的综合分析，几个先前报道 COPD蛋白生物标记物(CC16、表面活性蛋白D、SRAGE和PARC)，以及 COPD和COPD蛋白生物标记物能够预测轻到中度的疾病进展率 慢阻肺受试者。新的COPD蛋白生物标志物的鉴定和表征可能为 对COPD发病机制的洞察和未来临床试验的工具。

Project Summary/Abstract Current therapeutic options for chronic obstructive pulmonary disease (COPD) are limited, and new drug development in COPD has been hampered by the lack of clinically relevant biomarkers to assess likely drug efficacy. We will identify differentially abundant and lung-specific protein biomarkers of COPD in lung tissue and blood (plasma) using comprehensive proteomic analysis. Genetic determinants influence COPD susceptibility, but previously identified COPD genetic determinants account for only a small percentage of COPD heritability. Genetic analysis of protein biomarkers could reveal the network of regulatory factors influencing COPD susceptibility and COPD heterogeneity. Our overall hypothesis is that functional genetic variants lead to abnormal proteomic states that influence the development and heterogeneity of COPD. We will identify potential COPD biomarkers by studying lung-specific proteins that differ in lung tissue and plasma from 100 COPD cases and 50 smoking control subjects. We will then measure the most promising lung- specific plasma proteins in 1950 non-Hispanic White and African American COPDGene subjects with distinct imaging characteristics (airway-predominant COPD, emphysema-predominant COPD, and resistant smokers) to identify protein biomarkers associated with COPD and COPD subtypes. We will also perform genetic association analysis of lung-specific protein levels using whole genome sequencing data in these COPDGene subjects. Genetic determinants of protein biomarker levels will be tested for association with COPD susceptibility and COPD subtypes in multiple COPD populations. We will then determine whether the integrated analysis of the identified protein biomarkers of COPD susceptibility, several previously reported COPD protein biomarkers (CC16, Surfactant Protein D, sRAGE, and PARC), and the genetic determinants of COPD and COPD protein biomarkers enables prediction of disease progression rates in mild-to-moderate COPD subjects. The identification and characterization of novel COPD protein biomarkers may provide insights into COPD pathogenesis and tools for future clinical trials.