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

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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.