GRK4 and development of salt sensitivity

GRK4 与盐敏感性的发展

• 批准号: 7908700
• 负责人: Pedro A. Jose
• 金额: $ 43万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908700
• 关键词: 4p16.3; Accounting; Adenylate Cyclase; Adolescent; Adult; African American; Age; Award; Behavior Therapy; Blood Pressure; Budgets; C57BL/6 Mouse; Caucasians; Caucasoid Race; Cells; Child; Chinese Hamster; Chinese Hamster Ovary Cell; Chinese People; Complex; Congresses; Development; Diagnostic tests; Dietary Sodium; Disease; Diuretics; Dopamine D1 Receptor; Dopamine Receptor; Drug Formulations; Electrolytes; Embryo; Essential Hypertension; Ethnic group; Excretory function; Figs - dietary; G protein coupled receptor kinase; G protein-coupled receptor kinase 4; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Genetic Variation; Heart; Homeostasis; Human; Human Chromosomes; Hypertension; Hypotension; Inbred C57BL Mice; Individual; Intake; Japanese Population; Kidney; Knock-out; Laboratories; Legal patent; Life Style; Link; Morbidity - disease rate; Motivation; Mus; National Heart, Lung, and Blood Institute; Ovary; Pathogenesis; Pharmacogenomics; Pharmacotherapy; Phenotype; Protein Isoforms; Proximal Kidney Tubules; Psyche structure; Regulation; Reporting; Research; Resistance; Risk; Role; SJL Mouse; Sodium; Sodium Chloride; Stress; Sturnus vulgaris; Testing; Transgenic Mice; Transgenic Organisms; Tubular formation; Variant; Water; Work; cardiovascular risk factor; gene replacement; human subject; lectures; mortality; normotensive; overexpression; prevent; public health relevance; receptor function; salt intake; salt sensitive; saluretic

DESCRIPTION (provided by applicant): High sodium intake, independent of blood pressure, is associated with increased cardiovascular risk. However, the genetic cause(s) of salt sensitivity is not known. The definitive evidence to link genes to complex diseases, such as hypertension and salt sensitivity is the swapping of one phenotype for another. G protein-coupled receptor kinase 4 (GRK4) is the only gene postulated as causal of hypertension that fulfills this criterion, i.e., GRK4 gene variants produce salt sensitivity and hypertension in mice. GRK43 142V transgenic mice develop salt-resistant hypertension while GRK43 486V transgenic mice develop salt-sensitive hypertension. Depending upon the genetic background, overexpression of GRK43 wild type converts a salt- sensitive mouse (C57BL/6J) to a salt-resistant mouse while overexpression of GRK43 486V converts a salt- resistant mouse (SJL/J) to salt-sensitive mouse. The overall objective is to test the hypothesis that human GRK43 wild type imparts salt resistance while human GRK43 486V causes salt-sensitive hypertension. Aim 1 will test the hypothesis that human GRK43 wild type causes salt resistance by facilitating sodium excretion. This change in phenotype is due, in part, to human GRK43 wild type differential regulation of GPCRs (e.g., D1R and AT1R) involved in the control of renal NaCl transport and blood pressure. Aim 2 will test the hypothesis that human GRK43 486V causes salt-sensitive hypertension, in part, by impairing renal D1R function and enhancing AT1R expression. The effect of knockout of GRK4 and targeted gene replacement with human GRK43 wild type gene and variants (486V) in mice on the regulation of renal sodium excretion and blood pressure will be studied. These studies will enable the deciphering of the mechanism of salt sensitivity and its impact on blood pressure. A modest reduction in salt intake in children, adolescents, and adults results in an immediate decrease in blood pressure, with long term benefits. However, dietary sodium restriction may not be beneficial to all. Lifestyle changes lower blood pressure and reduces cardiovascular risk but motivation is a problem. Results from these studies may be important in formulating diagnostic tests, drug therapy (pharmacogenomics) and lifestyle modification. PUBLIC HEALTH RELEVANCE: Variants of a gene called GRK4 predict with 70-90% accuracy that blood pressure will rise with increased salt intake. Diuretics are more effective in lowering blood pressure in individuals with variants of this gene. Results from these studies will be beneficial in the formulation of diagnostic tests, as well as drug therapy (pharmacogenomics) and lifestyle modification.

描述（由申请人提供）：高钠摄入量与血压无关，与心血管风险增加相关。然而，盐敏感性的遗传原因尚不清楚。将基因与高血压和盐敏感性等复杂疾病联系起来的明确证据是一种表型与另一种表型的交换。G蛋白偶联受体激酶4（GRK 4）是唯一符合这一标准的被假定为高血压病因的基因，即，GRK 4基因变异体在小鼠中产生盐敏感性和高血压GRK 43 142 V转基因小鼠发生盐抵抗性高血压，而GRK 43 486 V转基因小鼠发生盐敏感性高血压。根据遗传背景，GRK 43野生型的过表达将盐敏感小鼠（C57 BL/6 J）转化为盐抗性小鼠，而GRK 43 486 V的过表达将盐抗性小鼠（SJL/J）转化为盐敏感小鼠。总体目标是检验人GRK 43野生型赋予盐抗性而人GRK 43 486 V引起盐敏感性高血压的假设。目的1将检验人GRK 43野生型通过促进钠排泄而引起盐抗性的假设。这种表型变化部分是由于人GRK 43野生型对GPCR的差异调节（例如，D1 R和AT 1 R参与肾脏NaCl转运和血压的调节。目的2将检验人GRK 43 486 V部分通过损害肾D1 R功能和增强AT 1 R表达而引起盐敏感性高血压的假设。将研究GRK 4的敲除和用人GRK 43野生型基因和变体（486 V）在小鼠中进行靶向基因置换对肾钠排泄和血压的调节的影响。这些研究将有助于破译盐敏感性的机制及其对血压的影响。适度减少儿童、青少年和成年人的盐摄入量会立即降低血压，并带来长期益处。然而，饮食钠限制可能并不对所有人都有益。生活方式的改变降低血压和心血管疾病的风险，但动机是一个问题。这些研究的结果对于制定诊断测试、药物治疗（药物基因组学）和生活方式改变可能很重要。一种名为GRK 4的基因变体预测血压会随着盐摄入量的增加而升高，准确率为70-90%。利尿剂在降低具有该基因变体的个体的血压方面更有效。这些研究的结果将有利于诊断测试的制定，以及药物治疗（药物基因组学）和生活方式的改变。