Structural Determinants of Disease Progression in COPD

COPD 疾病进展的结构决定因素

• 批准号: 10374005
• 负责人: Surya P. Bhatt
• 金额: $ 51.9万
• 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/10374005
• 关键词: 3-Dimensional; Adult; Affect; Alveolar; Anatomy; Area; Attenuated; Caliber; Cause of Death; Chronic Obstructive Pulmonary Disease; Clinical; Complex; Consumption; Cross-Sectional Studies; Data; Development; 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; base; 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; 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.

项目摘要/摘要 慢性阻塞性肺疾病（COPD）是肺的炎症性疾病，导致 气流限制；它影响了美国的2400万成年人，是死亡的第三大原因。最近的 研究挑战了COPD是统一进步的范式，但是构成了不同的机制 疾病进展的轨迹尚不清楚。疗法发展的主要障碍 改变疾病的进展是我们无法精确地具有疾病轨迹可变的表型个体。 可靠的替代生物标志物可以预测各个受试者的临床进展。此外，存在 药物疗法对呼吸道发病率有适中的影响，并且未能影响FEV1下降的速度。 这些药物针对气道音调和炎症，没有任何直接针对的结构变化涉及 FEV1改变的气道或肺泡重塑（肺气肿）。因此，理解的主要差距是 确定确定疾病的结构气道/牙槽重塑的相互依赖性途径 进展将为COPD提供更精确的诊断和治疗策略。 COPD的起源被认为是直径小于2毫米的小型导电道中 数据主要是横截面。此外，COPD的特征是气道重塑和肺泡 破坏；这两个过程可能有助于疾病的启动和进展。我们的初步发现 表明疾病进展是由于肺结构变化的复杂相互作用而发生的 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。 FEV1的变化和结构的进展并不能完全反映疾病进展 疾病是疾病轨迹的重要决定因素。基于这些发现，我们假设该结构 气道和牙槽室的解剖学和机械因素都导致疾病进展 COPD。 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的数据（遗传 COPD，COPDGENE和亚群的流行病学以及COPD研究中的中级结果指标， 螺旋胶质）具有5年的随访，其特定目的。本应用程序的目标1是确定 机械影响肺是否导致肺气肿的启动和进展。在AIM 2中，我们将确定 肺气肿的空间分布是否影响疾病进展。在AIM 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，建立新型成像生物标志物并帮助 创建精确的模型，以使更具靶向疗法的发展减轻疾病进展。