Striatin, Aldosterone and Hypertension

Striatin、醛固酮和高血压

• 批准号: 8505613
• 负责人: GORDON H WILLIAMS
• 金额: $ 81.76万
• 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/8505613
• 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; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genetically Modified Animals; Genotype; Goals; 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 Endothelial Cell; Vasodilator Agents; aldosterone hypertension; base; blood pressure regulation; dietary restriction; heart function; hypertension treatment; improved; non-genomic; novel; novel strategies; prevent; protein expression; public health relevance; receptor; response; salt intake; salt sensitive; 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 striatin 与两个因素之间的关联：醛固酮的作用机制和血管功能。Striatin 是一种胞质蛋白，据报道是雌激素非作用的关键中间体。 -基因组作用机制最近，我们记录了条纹蛋白：1）存在于多种心血管组织、单核细胞和肾上腺皮质中；2）是重要的调节因子。醛固酮在人类血管内皮细胞和单核细胞中的非基因组作用机制；3) 受醛固酮和钠摄入水平的调节；4) 基因多态性变异与人类盐敏感性高血压有关。醛固酮作用机制的调节剂，可能是血管功能的重要调节剂。此外，striatin 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。与条纹蛋白在介导醛固酮作用和/或分泌机制中的作用有关，这些新发现提供了入口。然而，该提案将仅关注其中两个：1）确定striatin在调节血管中的作用。 和心脏功能以及2）评估条纹蛋白在介导醛固酮生物合成中的作用这两个目标将使用三级转化方法（人类、转基因动物和细胞）在三个具体目标中进行评估。在高血压患者中，纹状体状态是血管功能和血管对 Na+ 摄入量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 striatin 基因变异的可预测性相关的三个假设：1）striatin 水平；2）非基因组和 striatin 蛋白对醛固酮和雌激素的反应；3）striatin 蛋白对 Na+ 摄入的反应。假设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介质，这些目标将通过评估来实现。 striatin+/+ 和 striatin+/- 小鼠，置于自由或 Na+ 限制饮食：1) 血压；2) 离体主动脉功能研究；3) 心脏、血管和肾上腺组织的体外分子研究；4) 原代内皮细胞培养物的分子研究和 5) 人类单核细胞研究。肾上腺细胞系将更直接地评估纹状体 因此，完成该项目的拟议目标，将确定 striatin 如何影响心血管功能、其与钠摄入量和醛固酮的相互作用，并可能提供促进作用。 e 预防和/或治疗高血压及其后果的有价值的新方法。