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