The purpose of this proposal is to identify the role of key signaling molecules in determining the proliferation or differentiation fate of basal cells during wound repair. The lung is one of few human organ systems to have direct contact with the external environment, a fact that necessitates extensive defense capacities. Upper respiratory diseases are the result of aberrant injury response signaling and defective wound repair. Basal cell-mediated wound repair occurs in two stages: 1) basal cell proliferation for the purpose of re-epithelialization, and 2) basal cell differentiation for development of a functional epithelium. My preliminary data indicate that stabilization of nuclear signaling by 2-catenin results in the development of an epithelium that lacks differentiated cells, and that decreased nuclear signaling by 2-catenin is permissive for basal cell differentiation. We hypothesis that cytoplasmic sequestration of 2-catenin is mediated by a tripartite complex composed of 14-3-3, chibby, and phospho-keratin 14 and is permissive for basal cell differentiation during wound repair. To test the central hypothesis, three Specific Aims are addressed in this proposal. 1) To test the hypothesis that monomeric keratin 14 is phosphorylated on threonine and serine residues in the 14-3-3 interaction domain, and phosphorylation is regulated by protein kinase C. 2) To test the hypothesis that interactions between 2-catenin, 14-3-3, and chibby regulate subcellular localization of 2-catenin. 3) To test the hypothesis that 2-catenin null basal cells do not differentiate into secretory or ciliated cells, resulting in basal cell hyperplasia and secretory and ciliated cell hypoplasia. This proposal seeks to better understand regulatory mechanisms involved in respiratory disease resolution vs. progression. The proposed studies are expected to provide mechanistic insight to basal cell signaling during wound repair. Knowledge of signaling events during wound repair may lead to novel targets by which to manipulate respiratory disease resolution/progression in the clinic.
Lung diseases such as bronchopulmonary dysplasia, chronic pulmonary disease, cystic fibrosis, asthma, and idiopathic pulmonary fibrosis are characterized by airway remodeling. In these diseases, there is often a component of aberrant wound healing, characterized by the loss of specialized (differentiated) cells and an increase in cells that exhibit a flattened morphology (non-differentiated basal cells). Insight into signaling mechanisms that promote basal cell differentiation may lead to therapeutic molecular targets that can be used to alleviate and/or resolve respiratory diseases associated with epithelial remodeling.
|Reynolds, Susan D; Brechbuhl, Heather M; Smith, Mary Kathryn et al. (2012) Lung epithelial healing: a modified seed and soil concept. Proc Am Thorac Soc 9:27-37|