Renal ion channels in the control of blood pressure

项目摘要 离子通道被公认为重要的治疗靶点，因为它们在控制 一系列非常广泛的生理过程。人类遗传学研究发现了一些基因突变 肾脏离子通道导致肾脏病理生理和血压异常改变。 了解肾脏离子通道调节的基本机制及其变化 调节网络导致的水和电解质失衡对于理解 高血压的发展，并设计新的战略来治疗这一毁灭性且代价高昂的疾病。 PI的研究小组在揭示控制几个离子的具体机制方面做出了关键贡献 肾脏经络及其在高血压发病中的作用。考虑到强大的历史背景 存在发现和商业化成功的药物的先例，这些药物调节细胞的活性 钠、钙或钾通道，并考虑到肾离子通道在控制 血压，新一代的治疗药物有望产生靶向离子通道在 肾脏。这项提议的中心原则是，几种类型的运输机，特别是ENaC， Kcnj10/Kcn16、TRPC6和Clcn6单独或在复杂、相互依赖的组合中工作 分别微妙地调节血压与钠尿的关系，控制血压。这个 上面列出的通道之所以被选择，是因为在编码这些基因的基因中报告了人类突变 通道，或它们被基因组广泛关联研究确定为与血液相关的基因 压力控制。通道及其调节器的基因组调制将在Dahl Salt- 敏感(SS)大鼠，一个特征明确的模型，它与盐敏感有许多共同的特征 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 概括了在非裔美国人中发现的高血压的主要表型。重要的是，党卫军模型有 顺从于强大的、尖端的遗传方法，成功地创建了多个突变模型， 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的 在我的实验室里开发的方法，我将能够系统地研究相应的关键变化 盐诱导高血压发生过程中的离子转运机制及其下游信号通路。 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，有助于我们理解肾离子通道在正常和慢性肾脏疾病中的作用 血压的病理生理控制。

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.