Hypertension (HTN) affects 25% of the adult population in the developed world and is a major, independent risk factor for stroke, myocardial infarction, and congestive heart failure. Several monogenetic defects resulting in HTN have now been attributed to abnormalities in sodium handling within the aldosterone-sensitive distal nephron where the epithelial Na+ channel, ENaC, constitutes the rate-limiting step of Na+ transport in the kidney. Therefore, elucidating the mechanisms of ENaC regulation will have profound pathophysiologic implications for the study of HTN. The proposed research will focus on the role of Nedd4- 2, SGK1, and 14-3-3 proteins in ENaC trafficking. The proposed experiments aim to: (1) Characterize the molecilar mechanisms by which Nedd4-2 regulates trafficking of ENaC. (2) Determine the subcellular localization of the specific 14-3-3 isoform(s) which interact with and inhibit Nedd4-2. (3) Evaluate the molecular mechanism of SGK1 and 14-3-3 regulation of Nedd4-2. In addition to the proposed experiments, didactic coursework in cell biology, confocal microscopy, and the responsible conduct of research will complement a structured mentorship training program to prepare the principal investigator (PI) for an academic career as a clinical scientist in Nephrology. Dr. David Pearce is a leader in the field of hormone regulation of ion transport and will mentor the Pi's scientific development. Additionally, Dr. Keith Mostov is a leader in the field of intracellular trafficking in epithelial cells and will provide scientific expertise in the design of experiments and interpretation of results. A professional development advisory committee comprised of accomplished biomedical scientists will also convene at regular intervals to provide scientific and career advice. The diverse, scientific resources and structured mentoring available at UC San Francisco are ideal for training clinical scientists. Within this training program and environment the PI will develop into a competitive, independent investigator.
| Chandran, Sindhu; Li, Hui; Dong, Wuxing et al. (2011) Neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) regulation by 14-3-3 protein binding at canonical serum and glucocorticoid kinase 1 (SGK1) phosphorylation sites. J Biol Chem 286:37830-40 |
| Hallows, Kenneth R; Bhalla, Vivek; Oyster, Nicholas M et al. (2010) Phosphopeptide screen uncovers novel phosphorylation sites of Nedd4-2 that potentiate its inhibition of the epithelial Na+ channel. J Biol Chem 285:21671-8 |
| Bhalla, Vivek; Soundararajan, Rama; Pao, Alan C et al. (2006) Disinhibitory pathways for control of sodium transport: regulation of ENaC by SGK1 and GILZ. Am J Physiol Renal Physiol 291:F714-21 |
| Bhalla, Vivek; Oyster, Nicholas M; Fitch, Adam C et al. (2006) AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2. J Biol Chem 281:26159-69 |
