The Human Distal Airway Aging Project

人类远端气道老化项目

• 批准号: 10083763
• 负责人: Renat Shaykhiev
• 金额: $ 64.5万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083763
• 关键词: 3-Dimensional; Address; Age; Aging; Architecture; Atlases; Biological; Caliber; Cause of Death; Cell Lineage; Cells; Cellular Assay; Chronic Obstructive Airway 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.

摘要。衰老与肺功能的进行性衰退和肺癌的发病率增加有关