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（BP）的盐敏感性是心血管（CV）发病率和死亡率的重要危险因素。 肾钠重吸收的不适当增加导致容量扩张、高血压（HTN）和盐 敏感BP（SSBP）。调节肾钠重吸收的关键稳态机制是：1）激素， 例如，在一个实施例中，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 在一个或两个机制导致HTN和SSBP。我们最近记录到，纹状体蛋白（STRN）发挥了一种新颖的作用， 在SSBP发展中的作用。然而，导致STRN介导的SSBP的机制尚不清楚; 界定这些机制是本提案的总体目标。纹状体蛋白是钙调蛋白和小窝蛋白结合蛋白， 可以充当支架和/或信号蛋白的蛋白质，特别是与类固醇相关的蛋白质 作用机制。在一个大型的特征明确的受试者队列中，我们记录了高血压和高血压性疾病， STRN风险等位基因携带者的血压正常人患有SSBP。然后，我们开发了一个STRN杂合子， 基因敲除（HET-KO）作为鉴定SSBP潜在机制的工具。我们记录了HET-KO小鼠 也有SSBP与较高的血压水平和不适当地增加ALDO水平在自由盐饮食。因此，在本发明中， 我们的总体假设是，STRN缺乏导致高盐饮食的血压升高，SSBP通过 对大量盐的摄入作出反应而损害正常的钠排泄。可能至少涉及两种机制 -1）血管舒张受损，特别是肾血管舒张受损，和2）ALDO分泌功能障碍， 行动上使用翻译方法，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将表现出血液中 压力与特定的醛固酮介导的治疗方法（盐皮质激素受体阻滞剂）比 用非特异性方法（STRN）; 2）假设：STRN缺乏导致过量的醛固酮 由于原发性肾小球功能障碍而对大量盐饮食作出反应的分泌;以及3） 假设：STRN缺乏损害了与自由盐相关的肾血流量的正常增加 摄入量增加，从而导致钠潴留、体积膨胀和血压升高。完成 这些目标将提高我们对STRN如何与两个主要的钠/容量稳态相互作用的理解 当盐摄入量改变时-ALDO分泌和肾血管舒张-以及STRN水平降低 导致不适当的钠潴留，导致SSBP和HTN风险增加。这些研究将 为有价值的新方法提供入口，以特异性预防和/或治疗HTN和CV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