Activation, injury and proliferation of airway and alveolar epithelial cells are critical to the development and/or repair of fibroproliferative lung diseases. Understanding the cell signaling cascades that occur in pulmonary epithelial cells and their causal relationship to these epithelial outcomes are vital to understanding the pathogenesis and these diseases and therapeutic strategies. The central hypothesis to be addressed in this Program pathogenesis of these diseases and therapeutic strategies. The central hypothesis to be addressed in this Program Project is that the mitogen-activated protein kinase (MAPK) cascades are causally linked to epithelial cell injury and proliferation in models of allergic airway hyperresponsiveness/fibrosis and asbestosis. Project #1 (Mossman) will define the role of extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs) in expression/transactivation of fos/jun (AP-1 family members) and their respective roles in epithelial cell proliferation in a murine inhalation model of asbestosis. Project #2 (Irvin) tests the hypothesis that activation of Nuclear Factor-kappaB (NF- kappaB) in bronchiolar epithelial cells plays an initiating role in inflammation in a murine model of allergic airway fibrosis, a consequence being inflammation and the elaboration of cationic proteins that trigger epithelial injury via MAPK pathways. Project #3 (Jaken) will elucidate the role of PKC in modulation of MAPK pathways, AP-1 transactivation, and epithelial cell proliferation in a murine model of asbestosis. Lastly, Project #4 (Heintz), using both models of fibrosis, will test the hypothesis, with a novel bacterial artificial chromosome (BAC) gene transfer technology, that activation of MAPK cascades leading to cell proliferation can be discriminated from those critical to cell injury by expression of cyclin D1 and the origin licensing factor cdc6. An Administrative Core (Mossman), an Inhalation/Transgenic Mouse Core (Hemenway/Rincon) and Cell Imaging and Analysis Core (Taatjes) will be critical to the success of all projects. All project and core leaders have pre-existing research collaborations and jointly authored publications. This multi-disciplinary team includes cell and molecular biologists, a physiologist, an inhalation toxicologist, a biostatistician, and an expert in approaches for development of transgenic mice.
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