Functional Genomic Biomarkers in COPD

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）影响着超过1800万美国人。很明显，这种衰弱综合征的主要环境风险因素是吸烟。然而，目前尚不清楚是什么因素导致了一些吸烟者患上这种疾病，而大多数人则没有。由于缺乏预测疾病进程的易于测量的特征，潜在治疗方法的研究受到阻碍。大多数研究使用肺功能的测量作为疾病活动的标志。此类研究通常需要大量患者和数月至数年的观察期。该申请提出了开发与COPD相关的替代生物标志物的研究。这项研究将开发一套候选生物标志物，通过利用表达阵列分析来表征与COPD相关的肺组织和外周血中的基因表达模式。这些候选人将在先前以COPD相关表型为特征的人群中进行的研究中进行评估：波士顿早发性COPD研究和规范性衰老研究。最初的研究将涉及从布莱根妇女医院接受肺切除术的患者中获得的肺组织和外周血样本中的表达谱。将来自20名肺量测定法显示气流阻塞和胸部CT扫描显示肺气肿的患者的样本与来自20名匹配的对照患者的样本进行比较。最先进的生物信息学分析技术将用于分析这些数据，并基于表达差异开发候选生物标志物列表。候选基因中的多态性将在两个具有不同疾病分布的特征人群中进行遗传关联研究。波士顿早发性COPD研究由在早期被诊断患有严重COPD的患者及其家庭成员组成。相比之下，规范老化研究包括患有广谱COPD的参与者。在这些人群中进行的研究旨在确定基因表达或基因多态性的差异是否与COPD相关。希望这些标志物将提供深入了解疾病的发病机制，并作为结果评估参数。

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) affects over 18 million Americans. It is clear that the major environmental risk factor for this debilitating syndrome is cigarette smoking. It is not clear, however, what factors are responsible for the fact that some smokers develop the disease while most do not. Studies of potential therapies have been hampered by the lack of easily measurable characteristics that predict the course of the disease. Most studies have used measures of lung function as a marker of disease activity. Such studies typically require large numbers of patients and an observation period of months to years. This application proposes studies to develop alternative biomarkers associated with COPD. The research proposed will develop a set of candidate biomarkers by utilizing expression array profiling to characterize gene expression patterns in lung tissue and peripheral blood associated with the presence of COPD. These candidates will then be assessed in studies performed in populations previously characterized for COPD-related phenotypes: the Boston Early Onset COPD Study and the Normative Aging Study. The initial studies will involve expressionprofiling in both lung tissue and peripheral blood in samples obtained from patients undergoing pulmonary resections at Brigham and Women's Hospital. Samples from 20 patients with airflow obstruction on spirometry and emphysema demonstrated on chest CT scans will be compared to samples from 20 matched control patients. State of the art bioinformatic analytic techniques will be used to analyze these data and develop a list of candidate biomarkers based on expression differences. Polymorphisms in the candidate genes will then be studied for genetic association in two characterized populations with different disease distributions. The Boston Early Onset COPD Study consists of patients who have been diagnosed at an early age with severe COPD and their family members. In contrast, the Normative Aging Study includes participants with a broad spectrum of COPD. Studies in these populations will be directed at establishing whether differences in gene expression or gene polymorphisms are associated with COPD. It is hoped that these markers will provide insight into disease pathogenesis and serve as outcome assessment parameters.