A large portion of the population is afflicted by the hypertensive and cardiovascular degenerative effects of AII. Because plasma levels of AII are often normal in the above disease states, abnormalities are likely to exist in receptor regulation and/or cell signaling, the mechanisms of which are complex and not fully understood. The applicant will use vascular smooth muscle cells in culture to i) define the C-terminal domain responsible for activation of phospholipase C; ii) investigate and identify the mechanisms of cross-talk by which the G-protein-coupled receptor activates MAPkinase via calcium calmodulin kinase; iii) identify receptor binding proteins responsible for receptor internalization and the mechanism of desensitization; and iv) down regulation of the AT1 mRNA by destabilization of the mRNA. The focus is on the dominant vasoconstrictor, mitogenic, hypertrophic receptor (AT1) and the regulatory function of the cytosolic C-terminal region. Techniques to be used include receptor antibodies, AT1 engineered mutant, the yeast two hybrid system, and specific new inhibitors and assay techniques. The approach using cellular and molecular tools will provide significant new information on complex receptor regulation and signaling and thus insights into potential defects in and therapy for various vascular diseases.
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