Cystic fibrosis is a common lethal genetic disease characterized by abnormal electrolyte transport in several epithelia. Defective electrolyte transport provides our current best insights into the cell biologic defect. In airway epithelia, defective regulation of apical membrane ion channels produces abnormally dehydrated respiratory tract fluid and impairs mucociliary clearance. As a result infection, inflammation, and injury destroy the airways producing bronchiectasis, the major cause of morbidity and mortality in the deceased. This application contains four projects which use basic and clinical research techniques to address the major abnormalities in CF. The main goal is to investigate the normal biology of airway epithelial cells and then to use that knowledge to understand the abnormal function and pathophysiology in CF. Previous work indicates that CF airway epithelia are chloride impermeable and have an increased rat of sodium absorption because of defective regulation of apical membrane ion channels. A major focus will be to understand the normal and abnormal regulation of such channels. Our second major focus is to understand the mechanisms of inflammation and injury in airway epithelia because the airway destruction. The collaborations and interactions of the four projects and the cell culture core provide interactive and novel approaches to understanding the disease.
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