Structural Determinants of Disease Progression in COPD

COPD 疾病进展的结构决定因素

• 批准号: 10593047
• 负责人: Surya P. Bhatt
• 金额: $ 52.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593047
• 关键词: 3-Dimensional; Adult; Affect; Alveolar; Anatomy; Area; Attenuated; Cause of Death; Chronic Obstructive Pulmonary Disease; Clinical; Complex; Consumption; Cross-Sectional Studies; Data; Development; Diameter; Dimensions; Disease; Disease Progression; Enrollment; Euclidean Space; Fractals; Growth; Heterogeneity; Image; Individual; Inflammation; Lung; Measures; Mechanics; Modeling; Outcome Measure; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Process; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Scanning; Severities; Shapes; Smoking Status; Spatial Distribution; Stretching; Surrogate Markers; Testing; Therapeutic; Thick; Time; United States; X-Ray Computed Tomography; airway obstruction; airway remodeling; alveolar destruction; clinical predictors; cohort; follow-up; genetic epidemiology; high risk; imaging biomarker; indexing; inflammatory lung disease; insight; mortality; mouse model; novel; personalized diagnostics; pulmonary function decline; respiratory morbidity; structural determinants; targeted treatment

Project Summary/ Abstract Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs that results in airflow limitation; it affects 24 million adults in the United States, and is the third leading cause of death. Recent studies challenge the paradigm that COPD is uniformly progressive, but the mechanisms that underlie distinct trajectories of disease progression are not well understood. A major hurdle in the advancement of therapies that alter the progression of disease is our inability to precisely phenotype individuals with variable disease trajectories; reliable surrogate biomarkers to predict clinical progression in individual subjects are lacking. Furthermore, existing pharmacotherapies have a modest impact on respiratory morbidity and fail to impact the rate of FEV1 decline. These medications target airway tone and inflammation, and none directly target structural changes involving the airways or alveolar remodeling (emphysema) that underlie FEV1 change. Thus, a major gap in understanding is the identification of inter-dependent pathways of structural airway/alveolar remodeling that determine disease progression which would inform more precise diagnostic and therapeutic strategies for COPD. The origins of COPD are believed to be in the small conducting airways less than 2 mm in diameter but these data are mostly cross-sectional. In addition, COPD is characterized by both airway remodeling and alveolar destruction; it is likely that both processes contribute to disease initiation and progression. Our preliminary findings suggest that disease progression occurs due to a complex interplay of structural changes in the lungs, both in the parenchyma and in the airways, including mechanical stretch of normal parenchyma, distribution of emphysema, and airway remodeling. Disease progression is not reflected entirely by FEV1 changes and progression of structural disease is an important determinant of disease trajectory. Based on these findings, we hypothesize that structural anatomic and mechanical factors in both the airway and alveolar compartments contribute to disease progression in COPD. To test these hypotheses, we will analyze data from two large well-characterized cohorts (Genetic Epidemiology of COPD, COPDGene, and Subpopulations and Intermediate Outcome Measures in COPD Study, SPIROMICS) with 5-year follow-up with the following specific aims. Aim 1 of this application will be to determine whether mechanically affected lung leads to initiation and progression of emphysema. In Aim 2, we will determine whether the spatial distribution of emphysema influences disease progression. In Aim 3, we will determine whether longitudinal changes in airway remodeling are associated with lung function decline. The results will identify mechanisms of disease progression, establish novel imaging biomarkers, and help create precise models that will allow development of more targeted therapies to attenuate disease progression.

项目概要/摘要 慢性阻塞性肺疾病 (COPD) 是一种肺部炎症性疾病，可导致 气流限制；它影响着美国 2400 万成年人，是第三大死因。最近的 研究挑战了慢性阻塞性肺病是一致进展的范式，但背后的机制不同 疾病进展的轨迹尚不清楚。治疗进展的一个主要障碍是 改变疾病的进展是因为我们无法精确地对具有可变疾病轨迹的个体进行表型分析； 缺乏可靠的替代生物标志物来预测个体受试者的临床进展。此外，现有的 药物疗法对呼吸系统发病率影响不大，并且无法影响 FEV1 下降率。 这些药物针对气道张力和炎症，但没有直接针对涉及气道的结构变化。 FEV1 变化背后的气道或肺泡重塑（肺气肿）。因此，理解上的一个主要差距是 确定决定疾病的结构性气道/肺泡重塑的相互依赖的途径 进展将为慢性阻塞性肺病更精确的诊断和治疗策略提供信息。 COPD 的起源被认为是直径小于 2 毫米的小气道，但这些 数据大多是横截面数据。此外，COPD 的特点是气道重塑和肺泡损伤。 破坏；这两个过程很可能都会导致疾病的发生和进展。我们的初步调查结果 表明疾病进展是由于肺部结构变化的复杂相互作用而发生的，无论是在 实质和气道，包括正常实质的机械拉伸、肺气肿的分布、 和气道重塑。疾病进展并不完全由 FEV1 变化和结构性进展反映 疾病是疾病轨迹的重要决定因素。基于这些发现，我们假设结构 气道和肺泡室的解剖和机械因素导致疾病进展 慢性阻塞性肺病。 为了检验这些假设，我们将分析来自两个大型特征良好的队列（遗传 COPD 的流行病学、COPD 基因、COPD 研究中的亚群和中期结果测量， SPIROMICS），并进行 5 年随访，具体目标如下。该应用程序的目标 1 是确定 机械性影响的肺部是否会导致肺气肿的发生和进展。在目标 2 中，我们将确定 肺气肿的空间分布是否影响疾病进展。在目标 3 中，我们将确定是否 气道重塑的纵向变化与肺功能下降有关。 结果将确定疾病进展的机制，建立新的成像生物标志物，并帮助 创建精确的模型，以开发更有针对性的疗法来减缓疾病进展。