Lab Research Focus
Our laboratory studies protein trafficking in the secretory and endocytic pathways. These pathways are critically important in cell biology since a number of diseases including familial hypercholesterolemia and cystic fibrosis result from protein sorting defects within these pathways. Our model protein is the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in cystic fibrosis (CF). This channel is present at the apical surface of a number of epithelial cell types and is responsible for anion transport. Cystic fibrosis is caused by the failure of epithelial cells to produce or deliver physiologically active CFTR channels to the apical surface of airway, intestinal, and pancreatic epithelia. The most common mutation in CF, DF508 (deletion of phenylalanine at the 508 position), results in a protein that is misfolded and degraded at the endoplasmic reticulum (ER) during biogenesis. Physiological studies have shown however, that the DF508 mutant channel partially retains its function when delivered to the cell surface. Therefore, we are testing different methods for releasing the DF508 CFTR protein from the ER as a possible therapeutic approach. Once DF508 CFTR reaches the surface, it appears to be more rapidly internalized and degraded than the wild type protein. Our main focus is to determine the molecular mechanisms that regulate the surface pool of CFTR and to establish how mutations in CFTR disrupt surface stability and biological function. Our hypothesis is that by understanding these cellular processes in detail, we will be able to develop biochemical methods for enhancing chloride channel function at the apical surface for a number of CFTR mutations. We utilize biochemical, morphological and physiological methods to accomplish these goals.
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