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

• 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
• 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

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.

项目摘要 慢性阻塞性肺疾病（COPD）是慢性呼吸症状的主要原因，差 美国和全球数百万人的生与死质量。在脆弱的人中，接触 2-3年以上的香烟烟雾导致固定的呼气气流阻塞，COPD的正弦原则。 尽管30-40％的吸烟者最终会发展COPD，但没有临床，生理，生物学或 在最早的疾病阶段，即COPD可以在COPD之前，可以识别出脆弱的人的分子措施 通过肺功能受损（早期COPD）诊断。这种无法在早期确定脆弱的人 COPD极大地限制了医生改变其课程的能力。该建议将解决这一关键研究 通过研究气道基底祖细胞的作用，差距并实现了COPD国家行动计划的主要目标 早期COPD检测，进展和发病机理的功能障碍。气道基底祖细胞是 对于肺部健康和维修至关重要。由于它们的复制能力（自我更新）并分化为所有人 上皮存在（多能性）中的细胞类型，气道祖细胞可以将受伤的上皮返回到 正常的结构和功能。来自年龄较大（约60岁）的人的初步数据表明，支气管和 在患有COPD的吸烟者，低正常肺功能的吸烟者中，鼻窦基底祖细胞功能降低， 在年轻的吸烟者（约40岁）中，没有已知的肺部疾病。这些发现暗示着祖先 功能在疾病发病机理中具有重要作用。使用散装和单细胞RNA的实验 测序，代谢组学和海马测量糖酵解通量和线粒体呼吸 确定能量代谢改变的强信号是祖先功能障碍的主要驱动力 具有COPD或低正常肺功能的吸烟者，以及祖先自我更新低的年轻吸烟者。 因此，我们假设Sinonasal和支气管祖细胞功能障碍是早期和 COPD的加速进展，以及早期COPD期间的祖细胞功能障碍与 细胞生物能源改变。我们将在没有70名年轻（30-50岁）吸烟者的情况下检验这一假设 祖细胞自我更新分层的肺部疾病，以高和低祖细胞功能。另外20 从不吸烟者没有已知的肺部疾病，有20名患有COPD的吸烟者将被招募为对照。目标1意志 使用横截面设计来确定支气管和鼻窦祖细胞功能障碍是标记 早期COPD。 AIM 2将使用纵向设计来确定是否需要支气管和鼻窦祖细胞 功能障碍是早期COPD期间疾病进展的标志。 AIM 3将确定是否支气管 和鼻窦祖细胞功能障碍与细胞生物能的改变有关。成功完成 在这些目标中，这些目标可能会通过在伤害之前将精力集中在预防疾病上，从而改变游戏规则的影响 不可逆的，促进使用缓慢肺功能下降的治疗方法，并通过识别早期机制 共同有可能挽救数百万生命的疾病。