. 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.
. Aging is associated with progressive decline in lung function and increased incidence of lung diseases, including chronic obstructive pulmonary disease (COPD), the 4th leading cause of death in the U.S. The proposed Human Distal Airway Aging (HDAA) project will comprehensively evaluate aging-associated biologic phenotypes, pathways and mechanisms in the human distal airways, which represent the primary site of both, aging-related and COPD-relevant changes in the human lung. The HDAA-associated COPD-relevant biologic patterns will be determined at the global, tissue-, and single- cell levels by comparatively analyzing distal airways from donors of different age with normal lung and with COPD, the cellular and molecular mechanisms underlying these HDAA patterns will be identified and therapeutically targeted using patient-derived distal airway organotypic models.
