Striatin, Aldosterone and Hypertension

描述（由申请人提供）：这是一份转化性研究计划，重点研究新发现的纹状蛋白与醛固酮的作用机制和血管功能之间的关联。纹状蛋白是一种细胞质蛋白，据报道是雌激素非基因组作用机制的关键中间体。最近，我们发现纹状蛋白：1)存在于几种心血管组织、单核细胞和肾上腺皮质；2)在人血管内皮细胞和单核细胞中是醛固酮非基因组作用机制的重要调节因子；3)受醛固酮和钠摄入量的调节；基因多态性变异与人类盐敏感性高血压有关。这些数据表明纹状蛋白是醛固酮作用机制的关键调节剂，可能是血管功能的重要调节剂。此外，纹状蛋白基因表达的变化可能参与调节血管对盐摄入量变化的反应，这可能与纹状蛋白在调节醛固酮作用和/或分泌机制中的作用有关。这些新发现为未来的研究开辟了几个途径。然而，本文将只关注其中的两个方面：1)确定纹状蛋白在血管调节中的作用

DESCRIPTION (provided by applicant): This is a translational research proposal focused on a newly identified association between striatin and two factors: aldosterone's mechanisms of action and vascular function. Striatin is a cytosolic protein that has been reported to be a criticl intermediate in estrogen's non-genomic mechanism of action. Recently, we have documented that striatin: 1) is present in several cardiovascular tissues, mononuclear cells and the adrenal cortex; 2) is an important regulator of aldosterone's non-genomic mechanism of action in human vascular endothelial and mononuclear cells; 3) is regulated by aldosterone and the level of sodium intake; 4) gene polymorphic variants are associated with salt sensitive hypertension in humans. These data suggest that striatin is a key modulator of aldosterone mechanisms of action and likely an important modifier of vascular function. Furthermore, variation in striatin gene expression may be involved in mediating vascular responses to changes in salt intake, potentially related to striatin's role in mediating aldosterone's mechanism of action and/or secretion. These novel findings provided entr¿e to several avenues for future studies. However, this proposal will focus only on two of them: 1) determining striatin's role in modulating vascular and cardiac function and 2) assessing striatin's role in mediating aldosterone biosynthesis. These two goals will be assessed in Three SPECIFIC AIMS using a three-level translational approach - humans, genetically modified animals, and cells. First, we will test the hypothesis that in hypertensives, striatin status is an important mediator of vascular function and vascular responses to changes in Na+ intake and aldosterone secretion. Second, in mononuclear cells from hypertensives we will test three hypotheses related to the predictability of striatin gene variants on: 1) striatin levels; 2) non-genomic and striatin protein responses to aldosterone and estrogen; and 3) striatin protein responses to Na+ intake. Third, we will test the hypothesis that in genetic modified mice and cells, striatin gene status is an important mediator of vascular function, vascular responses to changes in sodium intake and aldosterone secretion. These goals will be accomplished by assessing in striatin+/+ and striatin+/- mice, placed on a liberal or a Na+ restricted diet: 1) BP; 2) ex vivo aortic functional studies; 3) in vitro molecular studies i cardiac, vascular and adrenal tissue; 4) molecular studies in primary endothelial cell cultures and 5) mononuclear cells. Studies in a human adrenal cell line will assess more directly striatin's role in regulating aldosterone secretion. Thus, completing the proposed aims of this project, will define how striatin influences cardiovascular function, its interaction with sodium intake and aldosterone and may provide entr¿e to valuable new approaches to prevent and/or treat hypertension and its consequences.