The Human Distal Airway Aging Project

抽象的。衰老与肺功能进行性下降和肺部发病率增加有关 疾病，包括慢性阻塞性肺疾病(COPD)。越来越多的证据表明 早期肺老化事件以远端(或小)的功能/影像异常为主 航空公司。这与COPD尤其相关，对于COPD来说，远端呼吸道结构的紊乱， 伴随着前/末梢细支气管的消失和剩余小气道的重构，是一种典型的病理。 出现在肺气肿之前的特征，与呼吸道阻塞的严重程度相关。因此，它 COPD的发病机制可能与生理性肺老化有关。 创世纪。到目前为止，人们对远端气道炎的具体性质和生物学基础知之甚少。 在人的肺里。我们的初步数据显示，随着年龄的增长，远端呼吸道上皮(DAE)， 它覆盖了远端的气道腔表面，并由DAE驻留的基础干细胞维持 (BC)，获得了一种异常的近端呼吸道样转录组模式，并上调了一个独特的 一组BC基因及其改变的EGFR、FGFR、Notch、VEGF和炎性细胞的分子特征 电影信号。这些变化在45岁的健康受试者≥中表现明显，与吸烟有关。 ING与在COPD患者中观察到的DAE表型相似。此外，在我们的初步研究中， 我们已经建立了分离区域特异性BC和间充质细胞的方法学 在组织微域中评估该呼吸道区域的分子特征--以及SIN- 单细胞水平，并重建与衰老相关的、与COPD相关的远端呼吸道表型。 派生的器官类型模型。根据这些初步数据和方法，拟议的人类分布-- TAL呼吸道老化(HDAA)项目将系统地评估来自不同捐赠者的远端气道 不患有或患有慢性阻塞性肺病的年龄，以解决以下三个具体目标：目标1.组装分子- 人类远端气道老化的大图谱，并检验以下假设：随着年龄的增长，远端气道上皮 失去其区域特异性转录组模式，并获得COPD样基因表达表型。 目的2.评估与衰老相关的建筑和分化模式的空间分布 并验证衰老与获得异源基因有关的假设- 广泛分布的COPD相关的远端气道重塑表型。目标3.测试假设， 随着年龄的增长，远端气道基础干细胞再生正常分化的能力变得更弱。 而是产生COPD样的气道重塑表型，这是由于 他们与衰老相关的重新编程或改变了与间充质利基的串扰。在翻译中 AIM 3的分支机构，这些患者衍生的模型将作为临床前平台进行测试以进行识别 以及针对与衰老相关的COPD相关的远端气道重塑表型的治疗。

Abstract. Aging is associated with progressive decline in lung function and increased incidence of lung diseases, including chronic obstructive pulmonary disease (COPD). Accumulating evidence suggests that early lung aging events are dominated by functional/imaging abnormalities in the distal (or small) airways. This is particularly relevant to COPD, for which derangement of the distal airway architecture, with loss of pre-/terminal bronchioles and remodeling of remaining small airways, is a typical pathologic feature that occurs prior to emphysema and correlates with severity of airway obstruction. Therefore, it is possible that mechanisms underlying the physiological lung aging may be involved in COPD patho- genesis. So far, relatively little is known about the specific nature and biologic basis of distal airway ag- ing in the human lung. Our preliminary data show that with aging, the distal airway epithelium (DAE), which covers the distal airway luminal surface and is maintained by the DAE-resident basal stem cells (BC), acquires an aberrant, proximal airway-like transcriptome pattern, with up-regulation of a distinct set of BC genes and molecular features of altered EGFR, FGFR, Notch, VEGF and inflammatory cyto- kine signaling. These changes were apparent in healthy subjects ≥45 years old, associated with smok- ing and resembled the DAE phenotype observed in COPD subjects. Further, in our preliminary studies we have established the methodology to isolate region-specific BC and mesenchymal niche cells from human distal airways, evaluate molecular profiles of this airway region at tissue microdomain- and sin- gle-cell levels, and reconstruct aging-related, COPD-relevant distal airway phenotypes using patient- derived organotypic models. Based on these initial data and methodologies, the proposed Human Dis- tal Airway Aging (HDAA) project will systematically evaluate distal airways from donors of different age without or with COPD to address the following three Specific aims: Aim 1. Assemble the molecu- lar atlas of human distal airway aging and test the hypothesis that, with aging, distal airway epithelium loses its region-specific transcriptome pattern and acquires a COPD-like gene expression phenotype. Aim 2. Assess the spatial distribution of aging-related architectural and differentiation patterns in the human distal airways and test the hypothesis that aging is associated with acquisition of heterogene- ously distributed COPD-relevant distal airway remodeling phenotypes. Aim 3. Test the hypothesis that, with aging, distal airway basal stem cells become less capable of regenerating the normally differenti- ated distal airway epithelium, but instead produce COPD-like airway remodeling phenotypes, due to their aging-related reprogramming or altered crosstalk with the mesenchymal niche. In the translational branch of aim 3, these patient-derived models will be tested as pre-clinical platforms for identification and therapeutic targeting of aging-related COPD-relevant distal airway remodeling phenotypes.