COPD Is a growing problem worldwide. Most research to date has focused on the mechanisms of airspace inflammation and destruction. It has been presumed that repair is insufficient, but the mechanisms of repair, particularly cellular repair, have not been addressed. This proposal will support the Principle Investigator in the study of a recently described population of adult stem cells in the lung termed bronchioalveolar stem cells (BASCs). BASCs possess properties of both airway and alveolar epithelial cells. They have been shown to proliferate in airway and alveolar cell injury models and may contribute to both airway and alveolar repair. Our overall hypothesis is that BASCs are essential for alveolar maintenance and failure of BASCs to repair damaged alveoli in smokers contributes to emphysema. Moreover, BASCs use their repertoire of MMPs, particularly MMP-9, to repopulate the alveolar epithelium and basement membrane To address this hypotheses we propose to: (1) Apply transgenic lineage tagged BA$Cs to address the hypothesis that BASCs migrate into the alveolar space replacing alveolar type I and II cells in models of emphysema. We will use lineage tagged mice (CC10-CreXRosa 26 reporter mice) developed in our lab to evaluate BASC contribution to both cells types in the parenchyma. (2) Generate transgenic BASC lineage ablated mice to evaluate BASC ability to promote alveolar structural repair. We will generate a BASC deficient mouse by generating a transgenic CC10-CreXSPCLox-STOP-Lox-TK mouse in which BASCs, (that are CC-10+ and SPC+), will be specifically deleted with gancyclovir treatment. (3) Evaluate the role that MMP-9 plays in BASC migration and alveolar maintenance in models of emphysema. We will use wild type and MMP-9 deficient mice (generated in our lab) and BASC cells isolated from them to evaluate the role of MMP-9 in migration of BASC cells. Career Goals: This proposal and didactic learning will allow the P.I. to develop professional and technical skills to become a productive independent scientist. The scientific focus of lung stem cell biology and repair in emphysema represents a long-term career focus of significant importance to public health. Of note, learning how to create new transgenic tools will be of particular importance to the lung scientific community.
(See Instructions): COPD is a disease caused by the chronic inhalation of cigarette smoke which is epidemic worldwide, and predicted to be 3rd leading cause of death by 2020. To date, we have yet to translate our understanding of the pathogenesis into the development of disease modifying therapy. In addition, turning off the inflammatory, destructive processes can only prevent further lung deterioration but not restore lung function. In order to restore lung function, we address the process of repair and the basis for its failure in emphysema.
