Renal ion channels in the control of blood pressure

肾离子通道控制血压

• 批准号: 9242307
• 负责人: ALEXANDER STARUSCHENKO
• 金额: $ 38.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242307
• 关键词: Adult; African American; American; Blood Pressure; Calcium Channel; Complex; Coronary heart disease; Cost of Illness; Dahl Hypertensive Rats; Development; Electrolytes; Functional disorder; Generations; Genes; Genetic; Genetic study; Genomics; Goals; Homeostasis; Human; Human Genetics; Hypertension; Individual; Ion Channel; Ion Transport; Kidney; Kidney Failure; Laboratories; Lead; Link; Modeling; Mutation; Natriuresis; Pharmaceutical Preparations; Phenotype; Physiological Processes; Play; Potassium Channel; Rattus; Regulation; Reporting; Research; Risk Factors; Role; Signal Pathway; Sodium Channel; Sodium Chloride; Stroke; Therapeutic Agents; Variant; Water; Water-Electrolyte Imbalance; Work; blood pressure regulation; design; epithelial Na+ channel; genetic approach; genome wide association study; human disease; mutant; novel strategies; pressure; salt sensitive; salt sensitive hypertension; therapeutic target

Project Summary Ion channels are well recognized as important therapeutic targets because they play a crucial role in controlling a very wide spectrum of physiological processes. Human genetic studies identified a number of mutations in the renal ion channels leading to renal pathophysiology and abnormal changes in blood pressure. Understanding the basic mechanisms of ion channel regulation in the kidney and how alterations of such regulatory networks lead to water and electrolyte imbalance is fundamentally important for understanding of the development of hypertension and designing new strategies for treating this devastating and costly disease. The PI's research group has made key contributions in revealing specific mechanisms controlling several ion channels in the kidney and their contribution to the development of hypertension. Given the strong historical precedent that exists for discovering and commercializing successful drugs that modulate the activity of sodium, calcium, or potassium channels, and considering the critical role of renal ion channels in the control of blood pressure, new generations of therapeutic agents are expected to result from targeting ion channels in the kidney. The central tenet of this proposal is that several types of transporters, specifically ENaC, Kcnj10/Kcn16, Trpc6, and Clcn6, work either individually or in complex, interdependent combinations to delicately modulate the pressure natriuresis relationship and control blood pressure, respectively. The channels listed above were selected because either human mutations were reported in genes encoding these channels, or they were identified by Genome Wide Association Studies as genes associated with blood pressure control. Genomic modulation of channels and their regulators will be performed in the Dahl Salt- Sensitive (SS) rat, a well characterized and established model, which shares many features with salt-sensitive hypertension in humans. SS rat has been an enormously useful model as it is naturally occurring and recapitulates the major phenotypes found in hypertensive African Americans. Importantly, the SS model has been amenable to robust, cutting-edge genetic approaches to successfully create multiple mutant models, which will be used in this study. Considering the availability of these unique genetic rat models and novel approaches developed in my laboratory, I will be able to systematically study critical changes in corresponding ion transport mechanisms and downstream signaling pathways in the setting of salt-induced hypertension. The overall goal of this R35 proposal is to understand the impact of specific human gene variations on ion channel function and contribute to our understanding of the role of renal ion channels in normal and pathophysiological control of blood pressure.

项目摘要 离子通道被广泛认为是重要的治疗靶标，因为它们在控制中起着至关重要的作用 非常广泛的生理过程。人类遗传研究确定了许多突变 肾离子通道导致肾脏病理生理学和血压异常变化。 了解肾脏中离子通道调节的基本机制以及这种改变的改变 监管网络导致水和电解质不平衡对于理解 高血压的发展并设计了治疗这种毁灭性和昂贵疾病的新策略。 PI的研究小组在揭示控制多种离子的特定机制方面做出了重要贡献 肾脏中的渠道及其对高血压发展的贡献。鉴于历史悠久 发现和商业化成功的药物的先例 钠，钙或钾通道，并考虑肾离子通道在控制中的关键作用 血压，新一代的治疗剂预计将是由靶向离子通道导致的 肾。该提议的核心宗旨是几种类型的运输者，特别是ENAC， KCNJ10/KCN16，TRPC6和CLCN6单独或复杂的相互依赖组合起作用 细微地调节压力纳地尿的关系和控制血压。这 之所以选择上面列出的通道，是因为在编码这些的基因中报告了任何人类突变 通道，或通过基因组广泛的关联研究将其鉴定为与血液相关的基因 压力控制。通道及其调节剂的基因组调节将在Dahl盐中进行 敏感（SS）大鼠，一种具有良好特征和既定模型，具有许多特征，具有盐敏感的 人类的高血压。 SS大鼠一直是一个非常有用的模型，因为它是自然发生的，并且 概括了高血压的非裔美国人中发现的主要表型。重要的是，SS模型具有 适合坚固的尖端遗传方法，以成功创建多个突变模型， 这将在本研究中使用。考虑到这些独特的遗传大鼠模型和新颖的可用性 在我的实验室中开发的方法，我将能够系统地研究相应的关键变化 在盐诱导的高血压的情况下，离子传输机制和下游信号通路。 该R35提案的总体目标是了解特定人类基因变异对离子的影响 通道功能并有助于我们理解肾离子通道在正常和 血压的病理生理控制。