The long-term goal of this Program Project is to elucidate cellular and molecular mechanisms whereby vasoactive hormones contribute to blood pressure regulation. This approach necessitates a multidisciplinary group encompassing disciplines of cell and organ physiology, biochemistry, pharmacology, neuroscience and molecular biology which we have assembled. The Program stresses a broad application to the problem of receptor-effector coupling mechanisms employing human, animals, cells and subcellular organelles and emphasized the application of state-of- the-art technology. Studies at a molecular level include: a) purification and sequencing of receptors and enzymes; b) development of monoclonal antibodies and probes for in situ hybridization; c) determination of regulatory role of GTP-binding proteins kinases and phosphatases on transporters and key phospholipases involved in signal transduction; d) use of transgenic models to simulate human disease and investigate the potentiating role of lactogenic hormone on vascular reactivity and steroid biosynthesis. Investigation at a cellular level will employ fluorescent probes to explore signal transduction and cellular transport in brain, kidney epithelium, vascular smooth muscle and glomerular messangium. The projects can be broadly grouped into two areas that investigate central and peripheral mechanisms of blood pressure regulation. Those of relevance to peripheral sites of action include: 1) Project 1 which assesses mechanisms of AII-induced signal transduction in proximal tubular epithelium, the site of a novel class of AII receptors; 2) Project 2 involves purification and regulation of proximal tubular cytochrome P450 isozymes important to arachidonic acid metabolism and epithelial electrolyte transport; Project 3 that involves a detailed characterization of transport pathways in proximal tubular epithelium; and Project 4 involves purification of V-1 vasopressin receptor and assessment of the regulatory role in hypertension. Cores provide administrative, tissue culture and state-of-the-art instrumentation to enhance scientific merit of all projects.
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