Renal ion channels in the control of blood pressure

项目概要 离子通道被公认为重要的治疗靶点，因为它们在控制 非常广泛的生理过程。人类遗传学研究发现了许多突变 肾离子通道导致肾脏病理生理和血压异常变化。 了解肾脏离子通道调节的基本机制以及如何改变这种机制 调节网络导致水和电解质失衡对于理解 高血压的发展并设计治疗这种破坏性且代价高昂的疾病的新策略。 PI的研究小组在揭示控制多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。鉴于深厚的历史底蕴 发现调节活性的成功药物并将其商业化的先例 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，新一代治疗剂预计将通过靶向体内的离子通道而产生。 肾。该提案的中心原则是几种类型的转运蛋白，特别是 ENaC， Kcnj10/Kcn16、Trpc6 和 Clcn6 可以单独工作，也可以以复杂、相互依赖的组合方式工作， 分别微妙地调节压力尿钠关系和控制血压。的 选择上面列出的通道是因为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鉴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节将在达尔盐中进行 敏感 (SS) 大鼠，一种经过充分表征和建立的模型，与盐敏感大鼠具有许多共同特征 人类高血压。 SS 大鼠是一种非常有用的模型，因为它是自然发生的并且 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 能够采用强大的、尖端的遗传方法来成功创建多个突变模型， 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 在我的实验室开发的方法中，我将能够系统地研究相应的关键变化 盐诱发高血压中的离子转运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，有助于我们了解肾离子通道在正常和正常情况下的作用 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.