Goals of this proposal are to extend fundamental principles in lung stem cell biology for the development of effective strategies to amplify and purify lung stem cells, deliver them to repair deficient airways, and enhance epithelial reparative capacity. The underlying premise upon which this proposal is based is that defects in the reparative capacity of epithelial cells represent a common factor contributing to the progression of chronic lung disease, and that strategies aimed at enhancing epithelial reparative capacity will be essential components of treatments to effect lung regeneration. To achieve the goals of this proposal we have organized a research team drawing from basic and clinical scientists with expertise in stem cell biology, cell-based therapy, lung injury and repair, and the clinical management of chronic lung disease in humans. The scientific foundation for studies proposed in this application is based upon our previous demonstration that endogenous tissue stem cells are required for maintenance of epithelial reparative capacity, and that potentiation of b-catenin signaling in airways of mice leads to expansion of endogenous stem cells that harbor intrinsic reparative capacity. Accordingly, we hypothesize that pharmacologic interventions capable of transiently activating b-catenin signaling will lead to expansion of endogenous stem cells and enhanced epithelial reparative capacity, and that enriched populations of reparative cells obtained through potentiation of b-catenin signaling can be used for restoration of epithelial reparative capacity in repair-deficient recipient airways. Three aims are proposed that will build a platform upon which cell-based therapies can be further developed. Aim 1 will use transient activation of b-catenin signaling for the amplification of mouse and human airway stem cells. In Aim 2, we will define the cell surface phenotype of bronchiolar stem cells for the prospective purification and enrichment of airway stem cells. Finally, in Aim 3, we will test the feasibility of using amplified bronchiolar stem cells for the restoration of reparative capacity in repair-deficient airways. Accomplishing these aims will provide a rational foundation upon which to further develop strategies for the delivery of reparative cells to lung tissue for correction of epithelial repair defects.