The Human Distal Airway Aging Project

人类远端气道老化项目

• 批准号: 10335171
• 负责人: Renat Shaykhiev
• 金额: $ 63.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335171
• 关键词: 3-Dimensional; Address; Age; Aging; Architecture; Atlases; Biological; Caliber; Cause of Death; Cell Lineage; Cells; Cellular Assay; Chronic Obstructive Pulmonary Disease; Cytokine Signaling; Data; Dissociation; Distal; Elderly; Epidermal Growth Factor Receptor; Epithelial; Event; Fibroblast Growth Factor Receptors; Functional Imaging; Gene Expression; Heterogeneity; Histology; Human; Image; Immunofluorescence Immunologic; Incidence; Inflammatory; Lung; Lung diseases; Mesenchymal; Methodology; Modeling; Molecular; Molecular Profiling; Morphology; Natural regeneration; Nature; Organoids; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Peripheral Resistance; Phenotype; Physiological; Pulmonary Emphysema; Resolution; Sampling; Severities; Site; Smoker; Smoking; Spatial Distribution; Surface; Terminal Bronchiole; Testing; Tissue Sample; Tissues; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; age group; airway epithelium; airway obstruction; airway remodeling; base; comparative; laser capture microdissection; microCT; molecular phenotype; non-smoker; notch protein; pre-clinical; pulmonary function; reconstruction; regeneration potential; sex; single cell analysis; single-cell RNA sequencing; stem cell genes; stem cells; therapeutic target; transcriptome

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.

抽象。衰老与肺功能的进行性下降和肺栓塞的发生率增加有关。 慢性阻塞性肺疾病（COPD）。越来越多的证据表明 早期肺老化事件主要由远端（或小） 航空公司.这与COPD特别相关，对于COPD，远端气道结构的紊乱， 伴有前/终末细支气管的丧失和剩余小气道的重塑，是典型的病理性 在肺气肿之前发生的与气道阻塞严重程度相关的特征。因此 生理性肺老化的潜在机制可能参与COPD的病理过程， 创世纪到目前为止，对远端气道AG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，远端气道上皮（DAE）， 其覆盖远端气道腔表面并由DAE驻留的基底干细胞维持 (BC)获得异常的近端气道样转录组模式， 一组BC基因和改变的EGFR、FGFR、Notch、VEGF和炎性细胞因子的分子特征， 凯恩信号。这些变化在≥45岁的健康受试者中很明显，与吸烟有关。 与COPD受试者中观察到的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和间充质小生境细胞的方法， 人远端气道，在组织微域和sin-in处评估该气道区域的分子概况， gle-cell水平，并使用患者- 衍生器官型模型。根据这些初步数据和方法，拟议的人类疾病- TalalAirwayAging（HDAA）项目将系统地评估来自不同年龄供体的远端气道， 年龄没有或患有COPD，以解决以下三个具体目标：目标1。集合分子- 最大的人体远端气道老化图谱，并检验以下假设：随着年龄的增长，远端气道上皮细胞 失去其区域特异性转录组模式并获得COPD样基因表达表型。 目标二。评估老龄化相关的建筑和分化模式的空间分布， 人类远端气道和测试的假设，即老化与收购的异质基因- 慢性阻塞性肺病相关远端气道重塑表型。目标3。检验假设， 随着年龄的增长，远端气道基底干细胞再生正常分化的干细胞的能力变得更低， 活化的远端气道上皮，而是产生COPD样气道重塑表型，这是由于 它们与衰老相关的重编程或与间充质生态位的改变的串扰。沿平移 根据aim 3的分支，这些患者衍生模型将作为临床前平台进行检测， 和衰老相关COPD相关远端气道重塑表型的治疗靶向。