The purpose of this proposal is to test the overall hypothesis that allelic variation in the angiotensinogen gene causes a change in its function rendering it a hypertension-causing or -susceptibility gene, and that defined manipulation of the mouse genome can be used to test the physiological significance of genetic variants in the human AGT genes, and its interaction with environmental and genetic stressors. The studies proposed herein will provide mechanistic studies on the biological consequences of variations in the AGT gene and on the interaction of genetic and non-genetic factors that modulate the susceptibility to disease. We propose to examine common haplotypic variants of the AGT gene in pre-existing gene targeted mouse models in which identical genes differing only at the variant positions have been specifically targeted to the mouse genome in a way which allows direct comparison among genetic variants. In each case we will compare the effects of allelic variation in AGT on baseline blood pressure. Moreover, the contribution of each allelic variant on hypertension will be compared in mice induced to be hypertensive experimentally, in mice induced to become atherosclerotic, and in mice under environmental stressors such as a high sodium diet, high fat diet or with other risk factors such as obesity and atherosclerosis.. To accomplish this goal we will: 1) Characterize blood pressure in AGT mice in a genetic background containing either a dysregulated or tightly regulated human renin gene and in mice lacking the endogenous AGT gene, 2) Compare blood pressure in mice made genetically or experimentally hypertensive, in mice made genetically atherosclerotic or obese or challenged by other CVD risk factors such as a high salt or high fat diet. Finally in aim 3, we will examine common polymorphisms and haplotypes in the AGT promoter and enhancer to assess their physiological significance in AGT-expressing cells derived from the liver, brain and kidney, and in vivo.
These aims will allow us to assess the physiological importance of allelic variation in the AGT gene implicated as risk factors in the pathogenesis of human essential hypertension. ? ?
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