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，因为它们在控制细胞凋亡中起着至关重要的作用。 一个非常广泛的生理过程。人类基因研究发现了一些突变， 肾脏离子通道导致肾脏病理生理和血压的异常变化。 了解肾脏离子通道调节的基本机制，以及这种变化是如何发生的。 调节网络导致水和电解质失衡是从根本上重要的理解， 高血压的发展和设计治疗这种毁灭性和昂贵的疾病的新策略。 PI的研究小组在揭示控制几种离子的具体机制方面做出了关键贡献 肾脏中的通道及其对高血压发展的贡献。鉴于强大的历史 这是发现和商业化成功药物的先例， 钠、钙或钾通道，并考虑到肾离子通道在控制 血压，新一代的治疗剂预计将导致靶向离子通道中， 肾该提案的中心原则是，几种类型的运输机，特别是ENaC， Kcnj 10/Kcn 16、Trpc 6和Clcn 6单独或以复杂、相互依赖的组合起作用， 分别精细调节压力利钠关系和控制血压。的 选择上面列出的通道是因为在编码这些通道的基因中报告了人类突变， 通道，或者它们被全基因组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剂的基因组调节将在Dahl盐中进行- 盐敏感（SS）大鼠是一种成熟的动物模型，与盐敏感大鼠有许多共同的特点 人类的高血压SS大鼠是一个非常有用的模型，因为它是自然发生的， 概括了在高血压非裔美国人中发现的主要表型。重要的是，SS模型具有 一直服从强大的，尖端的遗传方法，成功地创建多个突变模型， 将用于本研究。考虑到这些独特的遗传大鼠模型和新的 在我的实验室开发的方法，我将能够系统地研究相应的关键变化， 盐诱导高血压的离子转运机制和下游信号通路。 这项R35提案的总体目标是了解特定人类基因变异对离子代谢的影响。 通道功能，并有助于我们了解肾离子通道在正常和 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.