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

项目摘要 慢性阻塞性肺疾病(COPD)是引起慢性呼吸道症状的主要原因 美国和世界各地数百万人的生命和死亡质量。在易受伤害的人中，暴露于 吸烟2-30年会导致固定的呼气气流阻塞，这是慢性阻塞性肺疾病的必要条件。 尽管30%-40%的吸烟者最终会患上COPD，但没有临床、生理、生物或 在疾病的最早阶段，即在COPD可以 被诊断为肺功能受损(早期COPD)。在早期无法识别易受伤害的人 COPD极大地限制了医生改变病情的能力。这项提案将解决这一关键研究 通过研究呼吸道基础前体的作用，差距和实现COPD国家行动计划的主要目标 早期COPD的检测、进展和发病机制方面的功能障碍。呼吸道基底祖细胞是 对肺部健康和修复至关重要。凭借其复制(自我更新)和分化为 细胞类型存在于上皮细胞(多潜能)，呼吸道祖细胞可以使受损的上皮细胞恢复到 结构和功能正常。来自老年人(~60岁)的初步数据显示，支气管和 慢性阻塞性肺疾病吸烟者、肺功能低正常者、 年轻吸烟者(~40岁)无已知肺部疾病。这些发现表明，先祖 功能在疾病发病机制中起着重要作用。使用块状和单细胞RNA的实验 糖酵解通量和线粒体呼吸的测序、代谢组学和海马氏测量 发现能量代谢改变的强烈信号是老年人祖细胞功能障碍的主要驱动因素 患有COPD或肺功能正常程度低的吸烟者，以及祖细胞自我更新能力低的年轻吸烟者。 因此，我们假设鼻窦和支气管祖细胞功能障碍是早期和 COPD进展加速，早期COPD期间祖细胞功能障碍与 改变了细胞生物能量学。我们将在70名年轻(30-50岁)吸烟者中测试这一假设 已知的肺部疾病通过祖细胞自我更新的高和低祖细胞功能来分层。额外的20 从未吸烟者、无肺部疾病者和20名患有COPD的吸烟者将被登记为对照组。目标1将 采用横断面设计确定支气管和鼻窦祖细胞功能障碍是否为标志物 早期慢性阻塞性肺疾病。Aim 2将使用纵向设计来确定支气管和鼻窦祖细胞 功能障碍是COPD早期疾病进展的标志。目标3将确定支气管炎 鼻鼻祖细胞功能障碍与细胞生物能量学改变有关。成功完成 这些目标中的一项可能会产生改变游戏规则的影响，将重点放在损害之前的疾病预防上 不可逆转，便于使用减缓肺功能下降的治疗方法，并通过确定早期机制 这些疾病加在一起有可能拯救数百万人的生命。

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.