Striatin, Aldosterone and Hypertension

Striatin、醛固酮和高血压

• 批准号: 8896234
• 负责人: GORDON H WILLIAMS
• 金额: $ 10万
• 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/8896234
• 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（由应用程序提供）：这是一项翻译研究建议，重点是裁缝和两个因素之间的新确定的关联：醛固酮的作用机理和血管功能。纹状体素是一种胞质蛋白，据报道是雌激素非基因组作用机理中的关键中间体。最近，我们记录了纹状体素：1）存在于几个心血管组织，单核细胞和肾上腺皮质中； 2）是醛固酮在人血管内皮和单核细胞中非基因组作用机理的重要调节剂； 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的盐灵敏性高血压有关。这些数据表明，纹状体素是醛固酮作用机理的关键调节剂，并且可能是血管功能的重要修饰符。此外，纹状体素基因表达的变化可能与介导对盐摄入变化的血管反应有关，这可能与纹状体素在介导醛固酮的作用机理和/或分泌方面的作用有关。这些新颖的发现为未来研究提供了几种途径。但是，该提案仅关注其中两个：1）确定纹状体素在调节血管中的作用 和心脏功能以及2）评估纹状体素在介导醛固酮生物合成中的作用。这两个目标将使用三级翻译方法（人类，转基因动物和细胞）进行三个特定目标评估。首先，我们将检验以下假设：在高血压中，纹状体素状态是血管功能和对Na+摄入量和醛固酮分泌变化的血管反应的重要介体。其次，在高血压的单核细胞中，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）裁缝水平； 2）对醛固酮和雌激素的非基因组和裁缝蛋白反应； 3）对Na+摄入的蛋白质反应。第三，我们将检验以下假设：在遗传修饰的小鼠和细胞中，纹状基因状态是血管功能的重要介体，对钠摄入量变化和醛固酮分泌的血管反应的重要介体。这些目标将通过评估纹状体蛋白+/+和纹状体蛋白+/-小鼠来实现，并放置在自由主义或 NA+限制饮食：1）BP； 2）离体反功能研究； 3）体外分子研究I心脏，血管和肾上腺组织； 4）在原代内皮细胞培养物和5）单核细胞中的分子研究。在人肾上腺细胞系中的研究将更直接地评估纹状体 在确定醛固酮分泌方面的作用。完成该项目的拟议目标，将定义纹状体素如何影响心血管功能，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提供入门。