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Renal ion channels in the control of blood pressure

肾离子通道控制血压

基本信息

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
项目类别：
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

项目摘要

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.

项目总结