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Airway Basal Progenitor Dysfunction in the Detection, Progression and Pathogenesis of Early COPD

气道基础祖细胞功能障碍在早期 COPD 的检测、进展和发病机制中的作用

基本信息

批准号：
10737267
负责人：
Moumita Ghosh
金额：
$ 70.45万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737267
关键词：
Acceleration Address Affect Age Airborne Particulate Matter Airway Disease Alveolus Bioenergetics Biological Biological Assay Biopsy Cause of Death Cessation of life Chronic Chronic Obstructive Pulmonary Disease Climacteric Clinical Cross-Sectional Studies Data Defect Detection Diagnosis Diffusion Disease Disease Marker Disease Progression Disease stratification Early identification Elderly Energy Metabolism Enrollment Environment Epithelium Exposure to Functional disorder Gene Expression Genus Hippocampus Goals Histologic Histology Impairment Inferior Kinetics Longitudinal Studies Lung Lung diseases Maps Measurement Measures Metabolic Mitochondria Molecular Morphology Outcome Oxidative Phosphorylation Pathogenesis Persons Phase Physicians Physiological Predisposition Primary Prevention Property Pyruvate Quality of life Questionnaires Research Respiration Respiratory Signs and Symptoms Risk Role Secondary Prevention Signal Transduction Smoker Smoking Structure Symptoms Testing Vulnerable Populations X-Ray Computed Tomography airway obstruction cell type chest computed tomography cigarette smoke cigarette smoke-induced cost design disorder control disorder prevention environmental tobacco smoke environmental tobacco smoke exposure epithelial injury experimental study exposure to cigarette smoke longitudinal analysis longitudinal design lung health lung repair metabolomics never smoker non-smoker progenitor pulmonary function pulmonary function decline regional difference resilience respiratory health response self-renewal single-cell RNA sequencing small airways disease smoking cessation stable isotope stem cells

项目摘要

Project Summary Chronic Obstructive Pulmonary Disease (COPD) is a major cause of chronic respiratory symptoms, poor quality of life and death for millions of people in the US and worldwide. In vulnerable people, exposure to cigarette smoke over 2-3 decades leads to fixed, expiratory airflow obstruction, the sine qua non of COPD. Although 30-40% of smokers will eventually develop COPD, there are no clinical, physiologic, biologic or molecular measures that identify vulnerable people during the earliest phase of disease, i.e. before COPD can be diagnosed by impaired lung function (Early COPD). This inability to identify vulnerable people during early COPD drastically limits the ability of physicians to alter its course. This proposal will address this key research gap and meet a major goal of the COPD National Action Plan, by studying the role of airway basal progenitor dysfunction in detection, progression and pathogenesis of early COPD. Airway basal progenitor cells are essential for lung health and repair. By virtue of their ability to replicate (self-renewal) and differentiate into all cell types present in the epithelium (multipotentiality), airway progenitors can return an injured epithelium to normal structure and function. Preliminary data from older (~60 years old) people showed that bronchial and sinonasal basal progenitor function is reduced in smokers with COPD, smokers with low-normal lung function, and in younger smokers (~40 years old) without known lung disease. These findings imply that progenitor function has an important role in disease pathogenesis. Experiments using bulk and single cell RNA sequencing, metabolomics, and Seahorse measurement of glycolytic flux and mitochondrial respiration identified a strong signal for altered energy metabolism as a prime driver of progenitor dysfunction in older smokers with COPD or low-normal lung function, and in younger smokers with low progenitor self-renewal. Therefore, we hypothesize that sinonasal and bronchial progenitor dysfunction a marker for early and accelerated progression of COPD, and that progenitor dysfunction during early COPD is associated with altered cellular bio-energetics. We will test this hypothesis in 70 younger (age 30-50 years) smokers without known lung disease stratified by progenitor self-renewal for high and low progenitor function. An additional 20 never smokers without known lung disease and 20 smokers with COPD will be enrolled as controls. Aim 1 will use a cross-sectional design to determine whether bronchial and sinonasal progenitor dysfunction are markers of early COPD. Aim 2 will use a longitudinal design to determine whether bronchial and sinonasal progenitor dysfunction are markers for disease progression during early COPD. Aim 3 will determine whether bronchial and sinonasal progenitor dysfunction are associated with altered cellular bioenergetics. Successful completion of these aims could have a game-changing impact by focusing efforts on disease prevention before damage is irreversible, facilitating use of treatments that slow lung function decline, and by identifying early mechanisms of disease that together have the potential to save millions of lives.