SPIROMICS II: Biological underpinnings of COPD heterogeneity and progression

项目总结 慢性阻塞性肺病(COPD)是美国第三大死因。没有医疗记录 治疗可以降低死亡率或减缓疾病进展，部分原因是COPD是一种异质综合征， 这阻碍了靶向治疗的发展。SPIROMICS研究招募了2982名参与者参加 对现在和以前吸烟者和不吸烟对照的3年纵向研究，对他们进行表型分析 临床、放射学和生物学以确定慢性阻塞性肺疾病的异质性来源。这个新项目将 延长SPIROMICS参与者的随访时间，进行支气管镜检查亚研究，并进行 加重分组研究，以测试三个具体目标。这些目标背后的首要前提是 COPD是一组不同的分子表型的结果，这些分子表型是不同的放射学检查的基础 (解剖)和临床(生理)表型；以及将分子表型与特定的 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。第一个目标是定义吸烟者的自然历史，尽管吸烟者有症状，但仍被保存下来 肺活量测定“，并描述这种情况下的呼吸道粘液异常。患有这种新疾病的患者 公认的情况不符合COPD的当前标准，但仍有症状，加重样 事件、活动受限和气道壁增厚，它们可能是真正意义上的 慢性阻塞性肺疾病（慢阻肺）。第二个目的是确定肺气肿的X线前驱病变(S)，并确定 慢性支气管炎、放射性呼吸道疾病和慢性呼吸道疾病进展的分子表型 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和 我们开发的基于炎症途径和肺微生物组的表型新方法 在SPIROMICS中。第三个目标是通过以下方式促进我们对COPD恶化生物学的理解 易患基线表型、加重诱因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 一项急性加重亚组研究中的炎症反应。我们的最终目标是使有针对性的方法能够 基于不同生物途径的COPD治疗和疾病修改 慢性阻塞性肺疾病的进展和恶化是其基础。

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.