Grant: Operating Grant

Our airways and other organs are lined by sheets of epithelial cells that secrete ions and fluid and defend against pathogens. Appropriate regulation of anion secretion is essential for health, as evidenced by the lethal disease cystic fibrosis (CF) in which there is too little chloride secretion, and cholera, in which there is too much. The control of secretion by hormones and neurotransmitters has been extensively studied, however the regulation during infection and inflammation is less well understood. CFTR (CF Transmembrane conductance Regulator) is the apical anion channel that malfunctions in CF and cholera. It mediates chloride and bicarbonate secretion when phosphorylated, and also modulates calcium signaling and the release of inflammatory mediators. This proposal is to study mechanisms that control apical CFTR channels during host defense against bacteria, using novel electrophysiological and fluorescence assays to examine transfected cell lines and highly differentiated airway epithelial cells from human lung transplant recipients. Studying novel mechanisms that control apical CFTR will provide new insight into secretion, calcium signaling and inflammatory mediators, and may identify potential therapeutic targets for the treatment of cystic fibrosis and other secretory diseases.