Salt Sensitive Hypertension and Striatin

盐敏感性高血压和Striatin

基本信息

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
项目类别：
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

项目摘要

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大危险因素。肾钠重吸收的不当增加导致体积膨胀，高血压（HTN）和盐敏感的BP（SSBP）。调节肾钠重吸收的关键稳态机制是：1）激素，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。功能障碍在一种或两种机制中，导致HTN和SSBP。我们最近记录了Striatin（Strn）扮演一本小说在SSBP的发展中的作用。但是，导致STRN介导的SSBP的机制尚不清楚。定义这些机制是该提案的总体目标。纹状体蛋白是一种钙调蛋白和小窝蛋白结合可以用作脚手架和/或信号传导蛋白的蛋白质，特别是与类固醇有关的蛋白质作用机理。在大量表征良好的受试者中，我们记录了这种高血压和 Strn风险等位基因携带者的正常人具有SSBP。然后，我们开发了一个Strn杂合子敲除（HET-KO）是确定SSBP潜在机制的工具。我们记录了het-ko小鼠还具有较高BP水平的SSBP，并且在自由盐饮食中不当提高ALDO水平。那，我们的总体假设是，Strn缺乏症会导致BP在自由盐饮食和SSBP上增加。响应自由盐的摄入而损害正常的钠排泄。至少可能涉及两个机制 –1）血管征障，尤其是肾脏脉管系统，2）功能失调的Aldo分泌和行动。使用翻译方法，我们将通过解决以下目的来检验总体假设：1）假设：人类高血压STRN风险等位基因载体将显示出血液的降低明显降低具有特定醛固酮介导的治疗方法（矿皮质受体阻滞）的压力，而不是采用非特异性方法（氨氯地平）； 2）假设：Strn缺乏导致超过醛固酮由于原发性Zona glomerulosa功能障碍而响应自由盐饮食的分泌； 3）假设：STRN缺乏症会损害与自由盐有关的肾血流的正常增加摄入量，从而导致钠保留率，体积膨胀和血压升高。完成这些目标将提高我们对Strn如何与两个主要钠/量体内稳态相互作用的理解当盐摄入变化时 - ALDO分泌和肾血管舒张 - 降低Strn水平导致不适当的钠保留率导致SSBP和HTN风险增加。这些研究将为有价值的新颖方法提供特定预防和/或治疗HTN和CV疾病的主菜--- 个性化医学。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。

DOI：
发表时间：
2019
期刊：
International journal of exercise science
影响因子：
0
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)
影响因子：
0
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
影响因子：
0
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