The overall objective of this proposal is to understand the cellular mechanisms of airway epithelia ion transport. Airway epithelia secrete chloride to regulate the quantity and composition of the respiratory tract fluid, an important component of pulmonary mucociliary clearance. The main emphasis of this work is on the regulation of the ion channels in tracheal epithelia and in understanding the mechanism of ion permeation through the membrane channels.
The specific aims of the proposal are; first, to understand the regulation of the apical membrane chloride channel. Specific emphasis will be on the role of cyclic AMP-dependent protein kinase, calcium, protein kinase C, and pH in regulation of the channel. The second main goal is focused on the basolateral membrane potassium channel. Preliminary studies indicate that the channel is regulated by calcium, however, an understanding of its regulation requires quantitation of the effect and examination of the possibility that other agents may interact with calcium to regulate overall channel activity. Because calcium regulates the channel, it will also be important to directly measure intracellular-free calcium concentrations in airway epithelial cells. To address these specific aims, cellular electrophysiologic techniques, including the patch-clamp technique, and optical techniques designed to measure intracelllar calcium will be used. The knowledge obtained in these studies may be of particular importance of our understanding the mechanism and regulation of chloride secretion under normal conditions and in diseases, such as cystic fibrosis. Cystic fibrosis is a disease characterized by a chloride impermeability in multiple epithelia.
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