The discovery of the molecular nature of the epithelial Na channel (ENaC) has rapidly lead to the understanding that defects in this molecular complex, or in the factors responsible for its regulation, contribute strongly to abnormal regulation of blood pressure. the most convincing evidence that abnormal function of t his channel complex can produce hypertension comes from patients with Liddle~s Syndrome, a rare genetic disorder that produces an activating mutation in one of the channel subunits. This O~Brien Center Program will examine the important factors determining the structure and regulation of this molecular complex in order to gain insight into how abnormalities in its regulation might contribute to NaCI-sensitive hypertension. the first project will address the role of ENaC in the collecting duct and uropithelium in regulating NA exception. the experiments will test the novel hypotheses that overactivity of ENaC in the inner medullary collecting duct mechanosesation to afferent renal nerve activity. The second project will focus on the developmental regulation of ENaC in the normal rat and in rat models of salt-sensitive and -resistant hypertension. In addition, using a mouse model incapable of producing endogenous glucocorticoids, experiments will examine specific hypotheses on the role of glucocorticoid hormone on ENaC expression during development. the third project will focus on the regulation of the human ENaC gamma subunit gene. The preliminary data indicate that the 5' flanking region contains promoter activity and that steroid sensitivity might e conferred by a non-traditional response mechanism. Information from this project could provide critical information on regions of the gene leading to abnormal regulation of this subunit in hypertensive populations. The fourth project will test the hypothesis that specific mutations known to cause overactivity of ENaC in Liddle~s Syndrome do so by altering the insertion and retrieval of the channel complex in the plasma membrane. The fifth project will examine the integrated effects of over- and under-expressing ENaC in intact mice using genetic manipulation. The experiments will test several predictions derived from experimental results in cell and organ systems. The experiments will also test some important hypotheses regarding the role of ENaC in high renin hypertension. The separate projects are tightly interwoven to produce an interdisciplinary focus on a critically important molecular complex that, when abnormal, is capable of producing significant human disease.
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