The major goal of this laboratory is to identify the molecular mechanisms responsible for producing for producing salt-sensitive hypertension. The models used for the proposed studies are the Dahl salt-sensitive (S) and salt resistant (R) strains. These strains have renal mechanisms of Na handling that participate in the pathogenesis of elevated blood pressure. The proposed studies take advantage of previous observations that the inner medullary collecting duct cells of Dahl S rats, when cultured on filters, transport twice as much Na as those of the Dahl R rat. The proposed experiments will combine this preparation with DNA microarray analysis and expression screening to address the following aims. First, differentially expressed genes in the cultured inner medullary collecting ducts will be identified and localized on the rat chromosome. Second, differentially expressed genes will be screened using the oocyte expression system to determine if they alter Na transport will be further characterized and their mechanism of action channel. Those that do alter Na transport will be further characterized and their mechanism of action ascertained. Finally, genes that are differentially expressed and affect Na currents in oocytes will be over- or under-expressed in mammalian cell models. The experiments will be design to take advantage of other components of this SCOR program to integrate candidate genes into models where the mechanisms of Na channel and blood pressure regulation can be better understood. This information should greatly accelerate the progress toward identifying the molecular causes of salt- sensitive hypertension and thus lead to improved strategies for identification, treatment, and prevention.
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