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1800多万美国人。很明显，吸烟是导致这种衰弱综合征的主要环境风险因素。然而，目前还不清楚是什么因素导致了一些吸烟者患上这种疾病，而大多数人没有。由于缺乏预测疾病进程的容易测量的特征，潜在治疗方法的研究一直受到阻碍。大多数研究都使用肺功能的测量作为疾病活动的标志。这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相关的替代生物标记物的研究。这项研究将开发一套候选生物标记物，利用表达阵列图谱来表征与COPD存在相关的肺组织和外周血中的基因表达模式。然后，这些候选者将在以前以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研究和标准老龄化研究。最初的研究将包括从布里格姆妇女医院接受肺切除的患者身上获得的肺组织和外周血样本中的表达谱。来自20名在肺活量测定和胸部CT扫描中发现有气流阻塞和肺气肿的患者的样本将与20名匹配的对照组患者的样本进行比较。最先进的生物信息学分析技术将被用于分析这些数据，并根据表达差异开发候选生物标记物的列表。然后，将研究候选基因的多态，以确定具有不同疾病分布的两个特征群体的遗传关联。波士顿早发性COPD研究包括在早期被诊断为严重COPD的患者及其家庭成员。相比之下，标准化的老龄化研究包括患有广泛COPD的参与者。在这些人群中的研究将致力于确定基因表达或基因多态的差异是否与COPD有关。希望这些标记物能够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.