The long term objective of this proposal is to gain insight into the molecular mechanisms of angiotensin II (All) action and their role in modulation of renal function. The complexity of the renin - angiotensin system has become more apparent in recent years as the multiplicity of receptor signaling cascades, and biological responses has emerged. This laboratory has made important contribution to our understanding of receptor classification, regulation, and function and proposes to continue this line of investigation. New observations suggest that All binds to multiple G- protein coupled receptor subtypes within the kidney, one of which differs pharmacologically from previously reported sites. In addition, renal All receptors appear to be coupled to multiple G-proteins some of which are selectively increased in a model of All-induced hypertension. Thus, the aims of this proposal are designed to test the hypothesis that exaggerated renal responses to All in genetic and non-genetic models of hypertension are due at least in part to differential phenotypic expression of G- proteins coupled to All receptor subtypes thereby facilitating hypertensiongenic signal transduction pathways. To address this hypothesis we must first have more information on All receptor-subtype distribution and interaction with specific G-proteins in renal cell types participating in blood pressure regulation.
Aim 1 - To determine the pharmacological and molecular basis for the All receptor subtypes distribution within the kidney.
Aim 2 - To identify the GTP binding proteins mediating All- induced signal transduction by the receptor subtypes present in the kidney.
Aim 3 - To ascertain the extent to which All receptor subtypes and G- protein interactions contribute to enhanced signal transduction early in tahe development of hypertension. A strength of this proposal is the variety of """"""""state-of-the-art"""""""" techniques that will be employed to test this hypothesis in the areas of molecular biology, biochemistry and cell physiology. The studies will make an important contribution to our understanding of the vascular biology of the renin-angiotensin system.
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