Striatin, Aldosterone and Hypertension

描述(由申请人提供)：这是一项转化性研究提案，重点关注纹状体蛋白和两个因素之间的新发现的联系：醛固酮的作用机制和血管功能。Striatin是一种胞浆蛋白，已被报道是雌激素非基因组作用机制的关键中间体。最近，我们发现纹状体蛋白：1)存在于多种心血管组织、单核细胞和肾上腺皮质中；2)是醛固酮在人类血管内皮细胞和单核细胞中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；4)基因多态变异与人类盐敏感型高血压有关。这些数据表明，纹状体是醛固酮作用机制的关键调节器，可能是血管功能的重要调节剂。此外，纹状体蛋白基因表达的变化可能参与介导血管对盐摄入量变化的反应，这可能与纹状体蛋白在调节醛固酮的作用和/或分泌机制中的作用有关。这些新的发现为未来的研究提供了几个途径。然而，这项提议将只关注其中的两个：1)确定纹状体蛋白在调节血管中的作用 和心脏功能，以及2)评估纹状体蛋白在调节醛固酮生物合成中的作用。这两个目标将使用三个层次的转换方法在三个具体目标中进行评估-人类、转基因动物和细胞。首先，我们将检验这一假设，即在高血压患者中，纹状体状态是血管功能和血管对Na+摄取和醛固酮分泌变化的反应的重要介质。其次，在高血压患者的单个核细胞中，我们将检验与纹状体基因变异的可预测性有关的三个假说：1)纹状体水平；2)非基因组和纹状体蛋白对醛固酮和雌激素的反应；以及3)纹状体蛋白对Na+摄入的反应。第三，我们将检验这一假设，即在转基因小鼠和细胞中，纹状体基因状态是血管功能、血管对钠摄入量和醛固酮分泌变化的反应的重要中介。这些目标将通过在条纹+/+和条纹+/-小鼠中进行评估来实现，放置在自由或 限钠饮食：1)BP；2)体外主动脉功能研究；3)心脏、血管和肾上腺组织的体外分子研究；4)原代内皮细胞培养的分子研究；5)单核细胞的分子研究。对人类肾上腺细胞系的研究将更直接地评估纹状体蛋白 在调节醛固酮分泌中的作用。因此，完成这一项目的拟议目标，将确定纹状体蛋白如何影响心血管功能，它与钠摄入量和醛固酮的相互作用，并可能为预防和/或治疗高血压及其后果提供有价值的新方法。

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.