Hypertension, a major public health problem afflicting more than 15% of the population, is the most significant risk factor in cardiovascular disease and major cause of heart failure, kidney failure and stroke. Since the renin-angiotensin system (RAS) plays a central role in salt and water homeostasis and the maintenance of vascular tone, each component of this system represents a potential candidate in the etiology of hypertension. This proposal will focus on the angiotensin II (Ang II) receptor, a component of the RAS, since these cell-surface receptors are responsible for mediating Ang II physiological effects. Recently, it was demonstrated that Ang 11 interacts with two pharmacologically distinct subtypes of Ang II receptors, AT1 and AT2. The complete characterization of the structural and biochemical properties of the AT1 and AT2 receptors and their genes is essential for the full understanding of the regulatory actions of Ang II and the potential role of these receptors in the pathogenesis of hypertension as well as other cardiovascular disorders. Currently, very little is known about the human AT1 and AT2 receptors (hAT1R and hAT2R) genes or how they are transcriptionally regulated and why multiple alternatively spliced mRNA transcripts are synthesized. Furthermore, little is known about the function or the signal transduction mechanism(s) of the hAT2R. Therefore, the long term goals of this project are to characterize the hAT1R and hAT2R genes and to investigate the molecular mechanisms that regulate the expression of these genes and to characterize the biochemical properties of the hAT2R.
The specific aims of this proposal are to: 1) Define the cis-regulatory mechanisms involved in selectively directing the transcription of the hAT1R and hAT2R genes by utilizing DNA-mediated gene transfer, 2) Test the hypothesis that the four distinct hAT1R mRNAs are differentially expressed, 3) Test the hypothesis that the four distinct hAT1R mRNA transcripts are translated with differential efficiencies in vitro and in vivo, 4) Test the hypothesis that hAT1R mRNAs which harbor exon 3 encode a novel hAT1R, and 5) Utilize the yeast two-hybrid system to investigate hAT2R signal transduction mechanism(s).
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