The Human Distal Airway Aging Project

人类远端气道老化项目

基本信息

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
项目类别：
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

项目摘要

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.

抽象的。衰老与肺功能的逐渐下降和肺部入射增加有关疾病，包括慢性阻塞性肺疾病（COPD）。积累的证据表明早期的肺老化事件由远端（或小）的功能/成像异常主导航空公司。这与COPD特别相关，COPD的远端气道建筑的演变，由于损失了前/末端支气管和剩余小气道的重塑，这是一种典型的病理在肺气肿之前发生的特征，与气道异议的严重程度相关。因此，它有可能导致物理肺衰老的机制可能与COPD病情有关创世纪。到目前为止，关于远端气道Ag-的特定性质和生物学基础知之甚少。在人类肺中。我们的初步数据表明，随着老化，远端气道上皮（DAE），覆盖远端气道腔表面，并由DAE居住的基本干细胞维持（BC），获得异常的，近端气道的转录组模式，并具有独特的上调 EGFR，FGFR，Notch，VEGF和炎症细胞的一组BC基因和分子特征 Kine信号传导。这些变化在≥45岁的健康受试者中显而易见，与烟有关在COPD受试者中观察到的DAE表型。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论人类远端气道评估该气道区域的分子谱在组织微域和sin- 使用患者 - 派生的器官模型。基于这些初始数据和方法，拟议的人类删除 TAL AIRWAY老化（HDAA）项目将系统地评估来自不同的捐助者的远端气道没有COPD的年龄以解决以下三个特定目的：AIM 1。组装分子。人类远端气道衰老的Lar Atlas，并检验以下假设，即随着老化的远端气道上皮失去其特定区域的转录组模式，并获得类似COPD的基因表达表型。目标2。评估与衰老相关的建筑和分化模式的空间分布人类远端气道，并检验了衰老与异种烯的获取有关的假设相关的COPD远端气道重塑表型。目标3。检验以下假设：随着衰老，远端气道碱性干细胞变得较少，无法再生通常不同的 - ATED远端气道上皮，但由于由于他们与衰老相关的重编程或与间充质小众的串扰。在翻译中 AIM 3的分支，这些患者衍生的模型将作为识别前平台进行测试和与衰老相关的COPD远端气道重塑表型的治疗靶向。