The major objective of this O'Brien Kidney Research Center is to identify the molecular mechanisms involved in the regulation of the epithelial Na channel (ENaC). The rationale for this approach is to broaden the scientific framework from which the mechanisms of salt-sensitive hypertension can be explored. This application includes three regular projects, and two pilot and feasibility studies. The themes of the regular projects converge on aspects of ENaC regulation. Project 1 will examine the mechanism for the increase in ENaC activity recently shown to be mediated via the carboxy terminus of the alpha subunit. The role of endogenous kinase activity and the relationship of four identified candidate proteins to this regulation will be explored. Project 2 will examine the mechanisms whereby the Nedd4 family of proteins alters the activity of ENaC. Specific experiments will be directed at the interactions between WW domains within Nedd4 proteins and their targets, the PY motif present in each of the ENaC subunits. Project 3 will use gene targeting to develop a mouse that can express Cre recombinase under the control of tamoxifen in the collecting duct principal cell. This mouse, which will be of potential use to many investigators, will be used to develop a mouse that lacks expression of the Nedd4-2 gene product specifically in those cells in a time dependent fashion. The phenotype will be examined under a variety of conditions predicted to produce derangements in blood pressure and electrolyte balance. A second objective of this O'Brien Center is to foster the development of promising young scientists who will make contributions to the understanding and treatment of kidney diseases. The Pilot and Feasibility Studies of two such investigators are included. One proposes to examine some specific aspects of a newly discovered protein expressed in the kidney that may be a Mg ion channel. The second proposes a novel approach to the treatment of renal cell carcinoma using adenoviral expression of TRAIL, a protein causing apoptosis of tumor cells. The O'Brien Center will interface with the program on the biology of ENaC/degenerins lead by Dr. Welsh and with the SCOR in the Molecular Genetics of Hypertension lead by Dr. Sigmund.
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