This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are collaborating in studies on the role of the serine/threonine kinase SGK (serum- and glucocorticoid-inducible kinase) in regulating the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel protein that is mutated in the fatal genetic disease cystic fibrosis. Co-expression of human SGK1 and CFTR in frog oocytes increases CFTR-mediated chloride currents. This effect is caused in part by increased trafficking of CFTR protein to the plasma membrane. More recently, we have found that mutations in putative functional domains of SGK1 further enhance the ability of this kinase to stimulate CFTR activity in oocytes. Similarly, we have evidence that SGK regulation of CFTR activity is involved in the physiological adaptation of killifish to seawater. Our observations suggest that specific inhibitors of protein-protein interactions mediated by the SGK1 PDZ-interaction motif may further enhance the effects of SGK1 on mutant forms of CFTR that retain some channel activity. Other mutations known to increase SGK activity by creating a constitutively active kinase or by eliminating a Nedd4-2 ubiquitination site also enhance CFTR currents in frog oocytes. We will test the hypothesis that mutations that increase SGK activity will enhance the stimulation of CFTR currents by zebrafish SGK in oocytes, and we will test whether the mutant zebrafish SGKs are lethal or cause gross developmental abnormalities in zebrafish embryos. The ultimate goal of these studies is to provide information addressing whether boosting CFTR function by manipulating SGK activity represents a viable therapeutic approach to treating cystic fibrosis in some patients.
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