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要危险因素。肾钠重吸收的不当增加导致容量扩张、高血压（HTN）和盐敏感血压（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，例如肾血管系统功能障碍。我们最近记录了 striatin (STRN) 在一种或两种机制中导致 HTN 和 SSBP 的作用。然而，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，Striatin 是一种钙调蛋白和小窝蛋白结合剂。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在一大群特征明确的受试者中，我们记录了高血压和 STRN 风险等位基因携带者的血压正常的人患有 SSBP，然后我们开发了 STRN 杂合子。敲除（HET-KO）作为识别 SSBP 潜在机制的工具我们记录了 HET-KO 小鼠。在自由盐饮食中，SSBP 的血压水平较高，并且 ALDO 水平不适当升高。我们的总体假设是，STRN 缺乏会导致自由盐饮食的血压升高和 SSBP 的升高由于大量盐摄入而损害正常的钠排泄可能至少涉及两种机制。 –1) 血管舒张功能受损，尤其是肾血管系统，以及 2) ALDO 分泌功能障碍使用转化方法，我们将通过实现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显着更大的血液减少特定醛固酮介导的治疗方法（盐皮质激素受体阻断）的压力比采用非特异性方法（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而对大量盐饮食产生的分泌；3) 假设：STRN 缺乏会损害与自由盐相关的肾血流量的正常增加摄入，从而导致钠潴留、容量扩张和完成血压升高。这些目标将提高我们对 STRN 如何与两个主要钠/体积稳态相互作用的理解当盐摄入量发生变化时，系统会发生变化——ALDO 分泌和肾血管舒张——以及 STRN 水平的降低导致不适当的钠潴留，导致 SSBP 和高血压风险增加。因此，这些研究将。为专门预防和/或治疗高血压和心血管疾病的有价值的新方法提供入口—— 个性化医疗。

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）

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：
影响因子：
0
作者：
Maris, Stephen A;Winter, Christa R;Paolone, Vincent J;Headley, Samuel A E
通讯作者：
Headley, Samuel A E

Gradual hypertension induction in middle-aged Cyp1a1-Ren2 transgenic rats produces significant impairments in spatial learning.

中年 Cyp1a1-Ren2 转基因大鼠的逐渐高血压诱导会对空间学习产生显着损害。

DOI：
发表时间：
2019-03
期刊：
影响因子：
2.5
作者：
Willeman, Mari N;Chawla, Monica K;Zempare, Marc A;Biwer, Lauren A;Hoang, Lan T;Uprety, Ajay R;Fitzhugh, Megan C;De Both, Matthew;Coleman, Paul D;Trouard, Theodore P;Alexander, Gene E;Mitchell, Kenneth D;Barnes, Carol A;Hale, Taben M;Huentelm
通讯作者：
Huentelm

Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case-control study.

分娩治疗和体重指数作为产后先兆子痫的危险因素：一项病例对照研究。

DOI：
发表时间：
2017-10
期刊：
影响因子：
0
作者：
Skurnik, Geraldine;Hurwitz, Shelley;McElrath, Thomas F;Tsen, Lawrence C;Duey, Stacey;Saxena, Aditi R;Karumanchi, Ananth;Rich;Seely, Ellen W
通讯作者：
Seely, Ellen W

Vascular Mineralocorticoid Receptor: Evolutionary Mediator of Wound Healing Turned Harmful by Our Modern Lifestyle.

血管盐皮质激素受体：伤口愈合的进化介质因我们的现代生活方式而变得有害。

DOI：
发表时间：
2019
期刊：
影响因子：
3.2
作者：
Biwer, Lauren A;Wallingford, Mary C;Jaffe, Iris Z
通讯作者：
Jaffe, Iris Z

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：
发表时间：
2019
期刊：
影响因子：
0
作者：
Huang, Yuefei;Ting, Pei Yee;Yao, Tham M;Homma, Tsuyoshi;Brooks, Danielle;Katayama Rangel, Isis;Adler, Gail K;Romero, Jose R;Williams, Jonathan S;Pojoga, Luminita H;Williams, Gordon H
通讯作者：
Williams, Gordon H