TGF-BETA, CHLORIDE CHANNELS AND APOPTOSIS OF AIRWAY EPITHELIAL CELLS

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Epithelial repair after an insult with allergens or toxicants consists of an initial phase of epithelial spreading and migration into the wound, followed by proliferation and differentiation to replace the columnar cells that have been lost. These processes are spatially and temporally regulated by local signals provided by growth factors and cytokines. TGF-~ plays an important role in the pathophysiology of chronic asthma including thickening of sub-epithelial basement membrane and airway remodeling. However, the underlying mechanisms are unclear. The studies in application will identify important determinants of sensitivity to TGF-~-induced apoptosis that involves cross-talk between pro- and anti-apoptotic proteins and CI- channels in airway epithelial cells. The long term goal of this project is to ascertain the effects that TGF-~ have on voltage-gated chloride currents in the airway epithelial cells and to examine the effect of immunomodulators. Such investigations would provide unique insights to the pathophysiologic process of chronic asthma and the means to prevent or reverse the disease.