Salt Sensitive Hypertension and Striatin

盐敏感性高血压和Striatin

• 批准号: 10323250
• 负责人: GORDON H WILLIAMS
• 金额: $ 83.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-20 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323250
• 关键词: Acute; Address; Adrenal Glands; Aldosterone; Amlodipine; Aorta; Binding Proteins; Blood Pressure; Blood Vessels; CYP11A1 gene; Calcium Channel Blockers; Calmodulin; Cardiovascular Diseases; Caveolins; Cell Line; Cells; Controlled Study; Data; Defect; Development; Diet; Double-Blind Method; Enzymes; Equilibrium; Estrogens; Excretory function; Female; Functional disorder; Genetic Markers; Genetic Variation; Genetically Engineered Mouse; Goals; Half-Life; Hormonal; Hormones; Human; Hypertension; Impairment; Individual; Kidney; Knock-out; Knockout Mice; Lead; Mediating; Mineralocorticoid Receptor; Morbidity - disease rate; Mus; Pathway interactions; Persons; Play; Production; Proteins; Randomized; Renal Blood Flow; Renal function; Renin-Angiotensin-Aldosterone System; Resistance; Risk; Role; Scaffolding Protein; Signal Transduction; Signaling Protein; Small Interfering RNA; Sodium; Sodium Chloride; Steroids; System; Technology; Testing; Vasodilation; Wild Type Mouse; Zona Glomerulosa; antagonist; base; blood pressure elevation; blood pressure reduction; cardiovascular risk factor; cohort; dietary salt; heart function; hypertensive; improved; in vivo; indexing; male; mortality; normotensive; novel; novel strategies; personalized medicine; precision medicine; prevent; primary outcome; receptor; response; risk variant; salt intake; salt sensitive; salt sensitive hypertension; secondary outcome; tool; translational approach

Salt sensitivity of blood pressure (BP) is a substantial risk factor for cardiovascular (CV) morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension (HTN) and salt sensitive BP (SSBP). Key homeostatic mechanisms that regulate renal sodium reabsorption are: 1) hormonal, e.g., renin-angiotensin-aldosterone (ALDO) system (RAAS) and 2) vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to HTN and SSBP. We recently documented that striatin (STRN) plays a novel role in the development of SSBP. However, the mechanisms that lead to STRN-mediated SSBP are not clear; defining these mechanisms is the overall goal of this proposal. Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to steroids’ mechanism of action. In a large cohort of well characterized subjects, we documented that hypertensive and normotensive humans who are STRN risk allele carriers have SSBP. We then developed a STRN heterozygous knockout (HET-KO) as a tool to identify potential mechanisms for the SSBP. We documented that HET-KO mice also have SSBP with higher BP levels and inappropriately increased ALDO levels on a liberal salt diet. Thus, our overall hypotheses are that STRN deficiency causes increased BP on a liberal salt diet and SSBP by impairing normal sodium excretion in response to a liberal salt intake. At least two mechanisms are likely involved –1) impaired vasorelaxation, particularly of the renal vasculature, and 2) dysfunctional ALDO secretion and action. Using a translational approach, we will test our overall hypotheses by addressing the following Aims: 1) Hypothesis: Human hypertensive STRN risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine); 2) Hypothesis: STRN deficiency leads to excess aldosterone secretion in response to a liberal salt diet because of primary zona glomerulosa dysfunction(s); and 3) Hypothesis: STRN deficiency impairs the normal increase in renal blood flow associated with a liberal salt intake, thereby, leading to sodium retention, volume expansion and an increase in blood pressure. Completion of these Aims will improve our understanding of how STRN interacts with two major sodium/volume homeostatic systems when salt intake changes –ALDO secretion and renal vasodilation– and that reduction in STRN levels causes inappropriate sodium retention resulting in SSBP and increased risk of HTN. Thus, these studies will provide entrée to valuable novel approaches to specifically prevent and/or treat HTN and CV disease--- personalized medicine.

血压盐敏感性是心血管疾病发病率和死亡率的重要危险因素。 肾脏钠重吸收的不适当增加会导致容量膨胀、高血压(HTN)和盐分 敏感血压(SSBP)。调节肾脏钠重吸收的关键动态平衡机制是：1)荷尔蒙， 例如肾素-血管紧张素-醛固酮(ALDO)系统(RAAS)和2)血管，例如肾血管系统。功能障碍 一种或两种机制导致HTN和SSBP。我们最近记录了纹状体蛋白(STRN)在一部小说中的作用 在SSBP开发中的作用。然而，STRN介导的SSBP的发生机制尚不清楚； 定义这些机制是本提案的总体目标。Striatin是一种钙调蛋白和小窝蛋白结合蛋白 可以作为支架和/或信号蛋白的蛋白质，特别是与类固醇有关的蛋白质。 作用机制。在一大群特征良好的受试者中，我们记录了高血压和 血压正常的STRN风险等位基因携带者有SSBP。然后我们开发出一种STRN杂合子 基因敲除(HET-KO)作为一种工具来确定SSBP的潜在机制。我们记录了HET-KO小鼠 也有血压水平较高的SSBP，以及在自由食盐饮食中不适当增加的Aldo水平。因此， 我们的总体假设是，STRN缺乏会导致自由食盐饮食的BP增加，SSBP增加 盐分摄入过多会影响正常的钠排泄。可能至少涉及两种机制 -1)血管松弛受损，特别是肾血管松弛；2)醛酸分泌功能障碍和 行动。使用翻译方法，我们将通过解决以下目标来测试我们的总体假设：1) 假设：人类高血压STRN风险等位基因携带者的血液降幅更大 血压与特定的醛固酮介导的治疗方法(盐皮质激素受体阻断)相比 使用非特异性方法(氨氯地平)；2)假设：STRN缺乏导致醛固酮过多 由于原发性肾小球带功能障碍，对自由盐饮食的反应(S)；和3) 假设：STRN缺乏损害了与自由盐相关的正常肾血流量增加 因此，摄入会导致钠滞留、容量膨胀和血压升高。完成 这些目标将提高我们对STRN如何与两种主要的钠/容量稳态相互作用的理解 盐摄入量改变时的系统--Aldo分泌和肾血管扩张--以及STRN水平的降低 导致不适当的钠滞留，导致SSBP和增加HTN的风险。因此，这些研究将 提供有价值的新方法，专门预防和/或治疗HTN和心血管疾病 个性化医疗。

项目成果

Enhanced Thrombotic Responses Are Associated With Striatin Deficiency and Aldosterone.

• DOI: 10.1161/jaha.121.022975
• 发表时间: 2021-11-16
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Gromotowicz-Poplawska A;Flaumenhaft R;Gholami SK;Merrill-Skoloff G;Chabielska E;Williams GH;Romero JR
• 通讯作者: Romero JR

Inner ear pathologies impair sodium-regulated ion transport in Meniere's disease.

• DOI: 10.1007/s00401-018-1927-7
• 发表时间: 2019-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Eckhard AH;Zhu M;O'Malley JT;Williams GH;Loffing J;Rauch SD;Nadol JB Jr;Liberman MC;Adams JC
• 通讯作者: Adams JC

Comparing the Changes in Blood Pressure After Acute Exposure to Tai Chi and Walking.

比较急性接触太极拳和步行后血压的变化。

• 发表时间: 2019
• 期刊: International journal of exercise science
• 作者: Maris,StephenA;Winter,ChristaR;Paolone,VincentJ;Headley,SamuelAE
• 通讯作者: Headley,SamuelAE

Renal Outcomes in Medically and Surgically Treated Primary Aldosteronism.

• DOI: 10.1161/hypertensionaha.118.11568
• 发表时间: 2018-09
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Hundemer GL;Curhan GC;Yozamp N;Wang M;Vaidya A
• 通讯作者: Vaidya A

Histone demethylase LSD1 deficiency and biological sex: impact on blood pressure and aldosterone production.

组蛋白去甲基酶 LSD1 缺乏和生物性别：对血压和醛固酮产生的影响。

• DOI: 10.1530/joe-18-0247
• 发表时间: 2019
• 期刊: The Journal of endocrinology
• 作者: Huang,Yuefei;Ting,PeiYee;Yao,ThamM;Homma,Tsuyoshi;Brooks,Danielle;KatayamaRangel,Isis;Adler,GailK;Romero,JoseR;Williams,JonathanS;Pojoga,LuminitaH;Williams,GordonH
• 通讯作者: Williams,GordonH