Remodeling of the airway epithelium is a common pathological feature in chronic lung disease and a predisposing factor in the development of lung cancer. Accordingly, understanding cellular and molecular mechanisms of epithelial maintenance and repair are fundamental to the development of improved therapeutic modalities for the treatment of chronic lung disease. Key findings from our earlier funding were that progenitor cell depletion results in the activation of latent airway stem cells to affect epithelial regeneration. The ensuing reparative process required tight regulation of stem cell proliferation, migration of nascent progenitor cells and regulation of cellular differentiation. These critical phases of epithelial regeneration were accompanied by stabilization of (-catenin and regulation of (-catenin/TCFdependent gene transcription. In this proposal we will test the hypothesis that activation of the Wnt/(-catenin signaling pathway in adult repairing airways is necessary for precise orchestration of cell proliferation, migration and differentiation among epithelial stem and progenitor cell pools.
Three specific aims are proposed. Experiments in Aim 1 will investigate dynamic regulation of genes involved in regulation of the Wnt/(-catenin pathway and downstream target genes during repair of progenitor cell depleted airways.
In Aim 2, we will use conditional transgenic/knock-out approaches to either potentiate or inhibit (-catenin signaling to define functional roles for pathway activation in the regulation of airway wound repair. Finally, direct roles for Wnt signaling in regulation of (-catenin stabilization and downstream signaling will be determined by interference with Wnt interaction with its bipartite LRP/Fzd receptor during airway injury and repair through conditional expression of a dominant secreted inhibitor, Dkk1. Completion of these aims will provide new insights into signaling mechanisms responsible for epithelial regeneration and remodeling in the normal and diseased lung, and identify new targets that may be exploited for therapeutic intervention. ? ?
| Chen, Huaiyong; Matsumoto, Keitaro; Brockway, Brian L et al. (2012) Airway epithelial progenitors are region specific and show differential responses to bleomycin-induced lung injury. Stem Cells 30:1948-60 |
| Hashimoto, Shuichi; Chen, Huaiyong; Que, Jianwen et al. (2012) *-Catenin-SOX2 signaling regulates the fate of developing airway epithelium. J Cell Sci 125:932-42 |
| Manzo, Nicholas D; Foster, W Michael; Stripp, Barry R (2012) Amphiregulin-dependent mucous cell metaplasia in a model of nonallergic lung injury. Am J Respir Cell Mol Biol 47:349-57 |
| Teisanu, Roxana M; Chen, Huaiyong; Matsumoto, Keitaro et al. (2011) Functional analysis of two distinct bronchiolar progenitors during lung injury and repair. Am J Respir Cell Mol Biol 44:794-803 |
| Snyder, Joshua C; Zemke, Anna C; Stripp, Barry R (2009) Reparative capacity of airway epithelium impacts deposition and remodeling of extracellular matrix. Am J Respir Cell Mol Biol 40:633-42 |
| Zemke, Anna C; Teisanu, Roxana M; Giangreco, Adam et al. (2009) beta-Catenin is not necessary for maintenance or repair of the bronchiolar epithelium. Am J Respir Cell Mol Biol 41:535-43 |
| Teisanu, Roxana M; Lagasse, Eric; Whitesides, John F et al. (2009) Prospective isolation of bronchiolar stem cells based upon immunophenotypic and autofluorescence characteristics. Stem Cells 27:612-22 |
| Snyder, J C; Teisanu, R M; Stripp, B R (2009) Endogenous lung stem cells and contribution to disease. J Pathol 217:254-64 |
| Chen, Huaiyong; Matsumoto, Keitaro; Stripp, Barry R (2009) Bronchiolar progenitor cells. Proc Am Thorac Soc 6:602-6 |
| Zemke, Anna C; Snyder, Joshua C; Brockway, Brian L et al. (2009) Molecular staging of epithelial maturation using secretory cell-specific genes as markers. Am J Respir Cell Mol Biol 40:340-8 |
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