Cystic Fibrosis Transmembrane Conductance Regulator
A major focus of our research is understanding protein-protein interactions that modulate the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel found in the lung and other epithelial tissues. CFTR mutations leading to trafficking and folding defects are the most common source of genetic disease among Caucasians. Our goal is to characterize the interaction of CFTR with binding partners that regulate trafficking and folding processes.
Design of CAL-selective inhibitors:
We have shown that CAL limits the post-maturational stability of the ΔF508-CFTR mutant, which is carried by ~90% of CF patients. Furthermore, this interaction is mediated by the CAL PDZ domain. More recently, we have demonstrated that the CAL:CFTR interaction is potentially susceptible to selective disruption. Current research is focused on the design and identification of inhibitors selective for the CAL PDZ binding site, and the evaluation of their therapeutic potential. Our work involves a combination of X-ray crystallography, NMR, fluorescence spectroscopy, high-throughput screening of small-molecule inhibitors, and electrophysiological studies of polarized epithelial cell monolayers.
Targeting Pseudomonas infections:
Due to impaired mucociliary clearance, chronic infection with Pseudomonas aeruginosa is major cause of CF morbidity. Our collaborators in the O'Toole and Stanton labs have identified Cif (CFTR Inhibitory Factor) as a Pseudomonas protein that further suppresses CFTR expression and may therefore facilitate airway colonization. We are studying the structure and function of Cif, using X-ray crystallography and enzyme-activity assays, in order to identify its physiological substrates and mechanism of action.
Understanding regulators of CFTR endocytic trafficking:
In collaboration with colleagues at the University of Pittsburgh, we are analyzing the role of proteins that interact with CFTR to control its endocytic uptake. Ultimately, these proteins may provide additional therapeutic targets.