Striatin, Aldosterone and Hypertension

Striatin、醛固酮和高血压

• 批准号: 8889806
• 负责人: GORDON H WILLIAMS
• 金额: $ 13.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889806
• 关键词: Acute; Adrenal Cortex; Adrenal Glands; Aldosterone; Anabolism; Animals; Blood Pressure; Blood Vessels; Brain; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chronic; Data; Endothelial Cells; Estrogens; Forearm; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genetically Modified Animals; Genotype; Goals; Health; Heart; Human; Hypertension; In Vitro; Intake; Kidney; Knockout Mice; Lead; Link; Mediating; Mediator of activation protein; Mineralocorticoid Receptor; Molecular; Mononuclear; Mus; Physiologic pulse; Process; Proteins; Rattus; Renal Blood Flow; Reporting; Research Proposals; Rodent; Role; Signal Transduction; Sodium; Sodium Chloride; Steroids; Stimulus; Study Subject; Testing; Tissues; Translational Research; Variant; Vascular Diseases; Vascular Endothelial Cell; Vasodilator Agents; aldosterone hypertension; base; blood pressure regulation; dietary restriction; genetic variant; heart function; hypertension treatment; improved; non-genomic; novel; novel strategies; prevent; protein expression; receptor; response; salt intake; salt sensitive hypertension; translational approach

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.

描述（由申请人提供）：这是一项转化研究提案，重点关注新发现的纹状体与两种因素之间的关联：醛固酮的作用机制和血管功能。纹状体蛋白是一种胞浆蛋白，据报道是雌激素非基因组作用机制的关键中间体。最近，我们已经证明纹状体：1）存在于几种心血管组织，单核细胞和肾上腺皮质; 2）是醛固酮在人血管内皮细胞和单核细胞中的非基因组作用机制的重要调节剂; 3）受醛固酮和钠摄入水平的调节; 4）基因多态性变体与人类盐敏感性高血压相关。这些数据表明，纹状体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介导醛固酮作用和/或分泌机制的作用有关。这些新的发现为未来的研究提供了几条途径。然而，这项建议将只集中在其中两个方面：1）确定纹状体蛋白在调节血管内皮细胞中的作用， 和心脏功能; 2）评估纹状体蛋白在介导醛固酮生物合成中的作用。这两个目标将在三个具体目标中使用三级转化方法-人类，转基因动物和细胞-进行评估。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+摄入和醛固酮分泌变化的反应的重要介质。其次，在高血压患者的单核细胞中，我们将测试与纹状体基因变异的可预测性相关的三个假设：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; 3）纹状体蛋白对Na+摄入的反应。第三，我们将测试的假设，在基因修饰的小鼠和细胞，纹状体蛋白基因的状态是一个重要的调解人的血管功能，血管反应的变化，钠摄入量和醛固酮分泌。这些目标将通过在纹状体蛋白+/+和纹状体蛋白+/-小鼠中进行评估来实现，所述小鼠被置于自由或开放的环境中。 限制钠+饮食：1）BP; 2）离体主动脉功能研究; 3）心脏、血管和肾上腺组织中的体外分子研究; 4）原代内皮细胞培养物中的分子研究和5）单核细胞。在人肾上腺细胞系中的研究将更直接地评估纹状体蛋白的 调节醛固酮分泌的作用。因此，完成本项目的拟议目标，将定义纹状体如何影响心血管功能，其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的有价值的新方法提供入口。