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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：
10585921
负责人：
ALEXANDER STARUSCHENKO
金额：
$ 57.02万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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/10585921
关键词：
Adult African American population American Blood Pressure Calcium Channel Complex Coronary heart disease Cost of Illness Dahl Hypertensive Rats Development Drug Modulation 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 Phenotype Physiological Processes Play Potassium Channel Rattus Regulation Reporting Research Risk Factors Role Signal Pathway Sodium Channel Sodium Chloride Stroke Therapeutic Agents Variant Water Work blood pressure control commercialization design epithelial Na+ channel genetic approach genome wide association study genome-wide analysis human disease hypertensive mutant novel strategies pressure 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

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapeutic effects of L-lysine in Dahl SS rats, a Model of Salt-Induced Hypertension.

L-赖氨酸对 Dahl SS 大鼠（盐诱发高血压模型）的治疗作用。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Dissanayake,LashodyaV;Levchenko,Vladislav;Palygin,Oleg;Staruschenko,Alexander
通讯作者：
Staruschenko,Alexander

Effects of Potassium Supplementation and Kir7.1 Knockout on Renal Function During the Progression of Salt-Sensitive Hypertension.

钾补充剂和 Kir7.1 敲除对盐敏感性高血压进展期间肾功能的影响。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Zietara,Adrian;Levchenko,Vladislav;Palygin,Oleg;Staruschenko,Alexander
通讯作者：
Staruschenko,Alexander

The Role of Angiotensin II in Glomerular Volume Dynamics and Podocyte Calcium Handling.