Common genomic mechanisms of disease across asthma and COPD

哮喘和慢性阻塞性肺疾病的常见基因组机制

• 批准号: 8457448
• 负责人: Stephanie A Christenson
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457448
• 关键词: Adrenal Cortex Hormones; Amphiregulin; Area; Asthma; Biological Response Modifiers; Bronchoscopy; Cause of Death; Cells; Chronic Obstructive Airway Disease; Clinical; Cluster Analysis; Conditioned Culture Media; Data; Data Set; Development; Disease; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Exhibits; Family; Family member; Gene Expression; Genes; Genomics; Goals; Health; Heterogeneity; Human; In Vitro; Individual; Inflammation; Inflammatory Response; Interleukin-13; Lead; Ligands; Linear Models; Mediating; Mediator of activation protein; Messenger RNA; Metaplasia; MicroRNAs; Molecular; Molecular Profiling; Mucous body substance; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Play; Prevalence; Process; Production; Public Health; Publishing; Regulation; Repression; Research; Role; Sampling; Smoke; Smoker; Smoking; Stimulus; TNF gene; Testing; Therapeutic; Tobacco smoke; United States; Up-Regulation; Work; airway hyperresponsiveness; airway obstruction; atopy; base; bronchial epithelium; cigarette smoking; clinical phenotype; clinically relevant; cohort; improved; in vivo; injured airway; insight; member; notch protein; novel; public health relevance; response; tool; transcriptomics; treatment strategy

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.

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是全球主要的健康问题。作为一种以气流受限和异常炎症反应为特征的疾病，它与哮喘在临床和病理上具有许多显著特征。然而，在了解COPD疾病的基本机制方面取得的进展不如哮喘。考虑到疾病重叠，调查哮喘的转录组特征是否也在COPD患者中表达是有吸引力的，因为这可能提供对这些潜在机制的洞察，并可能有助于预测对治疗的反应。在之前的工作中，我们实验室确定了IL-13相关炎症的三基因特征，该炎症在哮喘的病理和临床不同的亚表型（“TH 2高”表型）中诱导，并预测对现有疗法的反应。我们还鉴定了一个miRNAs家族，即miR-34/449家族，该家族在哮喘中受到抑制，这一发现在体外IL-13暴露中得到了复制。IL-13在至少一些COPD患者中被诱导，并且对体外和体内粘膜化生的发展是重要的，该过程也是COPD中的关键病理学发现。我们建议研究这些IL-13的转录组特征是否也见于COPD。我们将评估与“TH-2高”表型相关的三基因标签是否在COPD中过表达，以及它是否可以识别COPD中的临床相关亚群。为了实现这一点，我们将使用气道上皮mRNA微阵列数据，从一个队列的238例COPD和非COPD患者，应用无监督聚类方法。使用从未吸烟者、当前吸烟者和进一步吸烟者的队列，我们将进一步确定这种特征是否存在于单独的COPD相关气道损伤的情况中。我们还将在SPIROMICS研究中接受研究性支气管镜检查的受试者亚组中研究COPD中的miRNA改变，特别关注miR-34/449家族。我们将分析50名受试者（包括健康对照、健康的前吸烟者、健康的当前吸烟者、患有COPD的前吸烟者和患有COPD的当前吸烟者）的支气管上皮miRNA表达，并鉴定吸烟和COPD的差异表达miRNA。然后，我们将开发mRNA和miRNA的签名粘液化生使用COPD特异性介质的这一过程。我们将使用这些特征来探测mRNA和miRNA表达数据，以研究它们如何促进COPD。理想情况下，这项工作可以改善COPD的靶向治疗。