CFTR (Cystic Fibrosis Transmembrane conductance Regulator) is a small conductance Cl channel that is regulated by phosphorylation and gated by ATP hydrolysis. Mutations in the gene coding for CFTR result in the genetic disease cystic fibrosis. Our long-term research goals are to investigate how mutations in CFTR cause its defective functions at the single molecule level and to examine how pharmacological interventions circumvent dysfunction of the mutant protein. The current proposal is aimed to explore the biophysical and biochemical mecanisms of the R domain in CFTR.
The specific aims of this proposal are:
Aim1. To investigate the mechanism of glibenclamide effect in CFTR-dR gating. Specifically we will investigate how the absence of the R domain reveals another binding site for glibenclamide. We will also test other sulphonylurea drugs.
Aim 2. To investigate the role of the R domain in the functional defect of dF508, the most common mutation associated with cystic fibrosis disease. Specifically, we will investigate whether the deletion of the R domain can restore CFTR-dF508 channel function. We will combine electrophysiology methods with molecular biology methods to achieve these aims. Results from this work will not only shed light on the function of the R domain in CFTR, but will also provide invaluable information to help the understanding of the most commom disease associated mutation of the CFTR channel.
| Bompadre, Silvia G; Sohma, Yoshiro; Li, Min et al. (2007) G551D and G1349D, two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects. J Gen Physiol 129:285-98 |
| Ai, Tomohiko; Bompadre, Silvia G; Wang, Xiaohui et al. (2004) Capsaicin potentiates wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride-channel currents. Mol Pharmacol 65:1415-26 |
| Ai, Tomohiko; Bompadre, G; Sohma, Yoshiro et al. (2004) Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating. Pflugers Arch 449:88-95 |
