Common genomic mechanisms of disease across asthma and COPD

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是世界范围内的一个主要健康问题。作为一种以气流受限和异常炎症反应为特征的疾病，它在临床和病理上都与哮喘有许多显著的特征。然而，与哮喘相比，在了解COPD疾病的基本机制方面取得的进展较少。考虑到疾病的重叠，调查哮喘的转录特征是否也在COPD患者中表达是很有吸引力的，因为这可能提供对这些潜在机制的洞察，并可能有助于预测治疗反应。在之前的工作中，我们的实验室发现了IL-13相关炎症的三个基因特征，它是在一种病理和临床上不同的哮喘亚型(“TH2 High”表型)中诱导的，并预测对现有治疗方法的反应。我们还发现了一个miRNAs家族，miR-34/449家族，它在哮喘中受到抑制，这一发现在体外暴露于IL-13中也是重复的。IL-13在至少部分COPD患者中被诱导，并且在体外和体内的粘液化生的发展中起重要作用，这一过程也是COPD的一个关键病理发现。我们建议调查IL-13的这些转录转录信号是否也出现在COPD中。我们将评估与“TH-2高”表型相关的三基因信号在COPD中是否过度表达，以及它是否能够识别COPD中临床相关的亚群。为了实现这一点，我们将使用从238名患有和不患有COPD的患者队列中获得的呼吸道上皮基因微阵列数据，应用无监督聚类方法。使用从不吸烟者、当前吸烟者和再吸烟者的队列，我们将进一步确定这一特征是否仅存在于COPD相关性呼吸道损伤的环境中。我们还将研究COPD中miRNA的变化，特别是在SPIROMICS研究中将接受支气管镜检查的受试者中miR-34/449家族。我们将分析50名受试者(包括健康对照组、健康的既往吸烟者、健康的现任吸烟者、既往患有COPD的吸烟者和目前患有COPD的吸烟者)中支气管上皮miRNA的表达，并鉴定与吸烟和COPD的差异表达的miRNAs。然后，我们将使用COPD特异的这一过程的介体来开发粘液化生的mRNA和miRNA特征。我们将使用这些信号来探测mRNA和miRNA的表达数据，以调查它们是如何导致COPD的。理想情况下，这项工作可以改善COPD的靶向治疗。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a major health concern worldwide. As a disease characterized by airflow limitation and an abnormal inflammatory response, it shares many significant features with asthma, both clinically and pathologically. However, less progress has been made into understanding the fundamental mechanisms of disease in COPD than in asthma. Given the disease overlap, investigating whether transcriptomic signatures of asthma are also expressed in patients with COPD is appealing as this may provide insight into these underlying mechanisms and may assist in predicting response to therapies. In previous work, our lab identified a three-gene signature of IL-13 associated inflammation that is induced in a pathologically and clinically distinct sub-phenotype of asthma ("TH2 High" phenotype), and predicts response to existing therapeutics. We have also identified a family of miRNAs, the miR-34/449 family, that is repressed in asthma, a finding that is replicated with IL-13 exposure in vitro. IL-13 is induced in at least some patiens with COPD, and is important to the development of mucous metaplasia in vitro and in vivo, a process that is also a key pathologic finding in COPD. We propose to investigate whether these transcriptomic signatures of IL-13 are also seen in COPD. We will evaluate whether the three-gene signature associated with the "TH-2 High" phenotype is over-expressed in COPD, and whether it can identify clinically relevant subpopulations within COPD. To accomplish this we will use airway epithelial mRNA microarray data available from a cohort of 238 patients with and without COPD, applying an unsupervised clustering approach. Using a cohort of never, current, and further smokers we will, furthermore, determine if this signature is present in the setting of COPD- associated airway injury alone. We will also study miRNA alterations in COPD, focusing specifically on the miR-34/449 family, in a subset of subjects from the SPIROMICS study who will undergo research bronchoscopy. We will profile bronchial epithelial miRNA expression in a cohort of 50 subjects (consisting of healthy controls, healthy former smokers, healthy current smokers, former smokers with COPD, and current smokers with COPD) and identify differentially expressed miRNAs with smoking and COPD. We will then develop mRNA and miRNA signatures of mucous metaplasia using COPD-specific mediators of this process. We will use these signatures to probe the mRNA and miRNA expression data to investigate how they contribute to COPD. Ideally, this work could lead to improved targeted therapies in COPD.