SPIROMICS II: Biological underpinnings of COPD heterogeneity and progression

项目摘要 慢性阻塞性肺疾病（COPD）是美国第三大死亡原因。没有医疗 治疗降低死亡率或减缓疾病进展，部分原因是COPD是一种异质性综合征， 这阻碍了靶向治疗的发展。SPIROMICS研究招募了2，982名参与者， 3-对目前和以前的吸烟者和从不吸烟的对照者进行为期一年的纵向研究，对他们进行表型分析 在临床上、放射学上和生物学上识别COPD异质性的来源。这个新项目将 延长入组SPIROMICS的受试者的随访时间，进行支气管镜检查子研究， 急性加重子研究，以测试三个具体目标。这些目标的首要前提是， COPD是一组异质性分子表型的结果，这些表型是不同放射学特征的基础。 （解剖学）和临床（生理学）表型;以及将分子表型与特定 放射学和临床表型将确定与疾病恶化相关的关键生物学因素 和进步。第一个目的是定义“尽管保留了症状的吸烟者”的自然史 肺量测定法”并表征这种病症的气道粘液异常。新发现的患者 公认的疾病不符合COPD的当前标准，但仍有症状，加重样 事件，活动限制和气道壁增厚，他们可能有一个前兆条件，以真正的 慢性阻塞性肺病第二个目的是确定肺气肿的放射学前驱病变，并识别肺气肿的影像学特征。 慢性支气管炎、放射性气道疾病和 肺气肿这一目标将利用几种新的放射学方法来测量肺部疾病， 我们开发的基于炎症途径和肺部微生物组的表型分析新方法 在螺旋学上。第三个目标是通过以下方法来提高我们对COPD急性加重生物学的理解： 易感基线表型、加重触发因素和宿主炎症反应的分析。这一目标 将利用RNA测序方法同时测量呼吸道病原体和宿主 急性加重子研究中的炎症反应。我们的最终目标是实现有针对性的方法， COPD治疗和疾病调整基于异质性生物学途径， 是COPD进展和加重的基础。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US. No medical therapies reduce mortality or slow disease progression, in part because COPD is a heterogeneous syndrome, which hinders the development of targeted therapies. The SPIROMICS study enrolled 2,982 participants into a 3-year longitudinal study of current and former smokers and never-smoking controls, phenotyping them clinically, radiographically and biologically to identify sources of heterogeneity in COPD. This new project will extend follow-up of participants enrolled in SPIROMICS, perform a bronchoscopy substudy and perform an exacerbation substudy to test three specific aims. The overarching premise underlying these aims is that COPD is a consequence of a heterogeneous group of molecular phenotypes that underlie distinct radiographic (anatomic) and clinical (physiologic) phenotypes; and that linking molecular phenotypes to specific radiographic and clinical phenotypes will identify key biological factors associated with disease exacerbation and progression. The first aim is to define the natural history of “Smokers with symptoms despite preserved spirometry” and characterize the airway mucus abnormalities underlying this condition. Patients with this newly recognized condition do not meet current criteria for COPD but nonetheless have symptoms, exacerbation-like events, activity limitations and airway wall thickening and they may have a precursor condition to bona fide COPD. The second aim is to determine the radiographic precursor lesion(s) for emphysema, and identify the molecular phenotypes underlying progression of chronic bronchitis, radiographic airway disease and emphysema. This aim will leverage several novel radiographic methods for measurement of lung disease and new approaches to phenotyping based on inflammatory pathways and the lung microbiome that we developed in SPIROMICS. The third aim is to advance our understanding of the biology of COPD exacerbations through analysis of predisposing baseline phenotypes, exacerbation triggers and host inflammatory response. This aim will leverage RNA sequencing methods to simultaneously measure respiratory pathogens and the host inflammatory response in an exacerbation substudy. Our ultimate goal is to enable targeted approaches to COPD treatment and disease modification that are based on the heterogeneous biological pathways that underlie COPD progression and exacerbations.