Linking airway genomics to the pathogenesis and clinical heterogeneity of COPD

描述(由申请人提供)： 慢性阻塞性肺疾病(COPD)是美国第四大死亡原因，预计其死亡率在未来20年内将稳步攀升。在美国，这种情况每年导致超过70万人住院，导致每年200-260亿美元的医疗支出。目前还没有治愈COPD的方法，目前可用的有限的治疗方法主要是减轻症状，而不是扭转疾病或阻止其进展。虽然香烟烟雾在慢性阻塞性肺疾病中的作用是毋庸置疑的，但吸入烟雾导致疾病发病的机制仍不清楚。发展新的COPD诊断和治疗方法的主要障碍之一是COPD患者表现出的临床异质性。虽然COPD被定义为一种以气流受限为特征的疾病状态，但不完全可逆，但临床、放射和病理结果可能反映了不同的潜在分子和致病机制。香烟烟雾会导致整个呼吸道的“损伤区域”，而吸烟者在支气管镜检查时刷牙获得的支气管呼吸道细胞中的基因表达既反映了这种损伤，也反映了随后的疾病特异性过程。这项建议检验了这样一种假设，即确定患有和不患有COPD的个体的呼吸道上皮细胞基因表达谱将为COPD的分子发病机制和特定的COPD相关特征提供见解，包括气流阻塞程度、肺气肿、小气道疾病和疾病进展率。呼吸道基因和microRNA表达的改变将被用来定义受COPD干扰的潜在途径，并定义可能有助于疾病临床多样性的COPD新的分子亚类。呼吸道基因表达的模式将与肺功能的纵向下降有关，从而提供一种方法来识别有快速疾病进展风险的个人，并了解导致其功能下降速度变化的机制。COPD相关呼吸道基因表达谱在肺组织内疾病进展过程中的表达如何变化将阐明与疾病相关的动态过程。这些基因表达变化在各种现有的和新的COPD药物治疗后的可逆性将决定呼吸道基因表达特征是否可以作为评估COPD治疗的中间标志物。最后，识别影响导致COPD特异性基因表达变化的潜在途径的可遗传遗传变异，并测试它们识别COPD风险个体的能力，将产生疾病易感性和进展的遗传标记。这项拟议的工作将强大的全基因组外显子水平和microRNA表达平台以及各种新的计算方法应用于一系列大型、独特和特征良好的现有队列的样本，并将导致对COPD发病机制的分子过程进行前所未有的详细观察。(摘要结束)

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and its mortality rate is expected to climb steadily over the next 20 years. In the US, this condition causes over 700,000 hospitalizations per year and leads to $20-26 billion in annual health care expenditures. There is currently no cure for COPD, and the limited therapies currently available mainly reduce symptoms rather than reverse the disease or prevent its progression. While the role cigarette smoke plays in COPD is undisputed, the mechanism by which inhaled smoke contributes to disease pathogenesis remains unclear. One of the major barriers to the development of new approaches to diagnose and manage COPD is the clinical heterogeneity displayed by COPD patients. While COPD has been defined as a disease state characterized by airflow limitation that is not fully reversible, there are diverse clinical, radiographic, and pathologic findings that likely reflect different underlying molecular and pathogenic disease mechanisms. Cigarette smoke causes an airway-wide "field of injury", and gene expression in bronchial airway cells of smokers obtained by brushings at bronchoscopy reflects both this injury and subsequent disease-specific processes. This proposal examines the hypothesis that determining the gene-expression profile of airway epithelial cells in individuals with and without COPD will provide insights into the molecular pathogenesis of COPD and specific COPD-related traits, including degree of airflow obstruction, emphysema, small airways disease, and the rate of disease progression. Alterations in airway gene and microRNA expression will be used to define the underlying pathways that are perturbed by COPD, and to define novel molecular subclasses of COPD that may contribute to the clinical diversity of the disease. Patterns of airway gene expression will be linked to longitudinal decline in lung function, providing a way to identify individuals at risk for rapid disease progression and an understanding of the mechanisms responsible for variations in their rate of functional decline. How the expression of COPD-related airway gene-expression profiles change during disease progression within lung tissue will elucidate dynamic disease-related processes. The reversibility of these gene expression changes upon treatment with various existing and novel COPD drugs will determine whether airway gene expression signatures can serve as an intermediate marker for evaluating COPD treatments. Finally, the identification of heritable genetic variants that influence the underlying pathways that are responsible for COPD-specific gene expression changes, and testing their ability to identify individuals at risk for COPD, will result in genetic markers of disease susceptibility and progression. The proposed work applies powerful whole-genome exon level and microRNA expression platforms and a variety of novel computational methodologies to samples from a series of large, unique, and well-characterized existing cohorts, and will result in an unprecedented and detailed view of the molecular processes that contribute to COPD pathogenesis. (End of Abstract)