GRK4 and development of salt sensitivity

GRK4 与盐敏感性的发展

• 批准号: 7658921
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658921
• 关键词: 4p16.3; Accounting; Adenylate Cyclase; Adolescent; Adult; African American; Age; Award; 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; Modification; 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 (GRK4) 是唯一满足这一标准的被假定为高血压病因的基因，即 GRK4 基因变异会在小鼠中产生盐敏感性和高血压。 GRK43 142V转基因小鼠出现耐盐性高血压，而GRK43 486V转基因小鼠则出现盐敏感性高血压。根据遗传背景，GRK43 野生型的过度表达会将盐敏感小鼠 (C57BL/6J) 转化为耐盐小鼠，而 GRK43 486V 的过度表达会将耐盐小鼠 (SJL/J) 转化为盐敏感小鼠。总体目标是检验以下假设：人 GRK43 野生型赋予耐盐性，而人 GRK43 486V 导致盐敏感性高血压。目标 1 将检验人类 GRK43 野生型通过促进钠排泄而导致耐盐性的假设。这种表型的变化部分是由于人类 GRK43 野生型对 GPCR（例如 D1R 和 AT1R）的差异调节，这些 GPCR 参与了肾脏 NaCl 转运和血压的控制。目标 2 将检验人类 GRK43 486V 部分通过损害肾 D1R 功能和增强 AT1R 表达而导致盐敏感性高血压的假设。将研究在小鼠中敲除GRK4并用人GRK43野生型基因和变体(486V)进行靶向基因替换对肾钠排泄和血压调节的影响。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。儿童、青少年和成人适度减少盐摄入量可以立即降低血压，并具有长期益处。然而，限制饮食钠摄入可能并不对所有人都有益。生活方式的改变可以降低血压并降低心血管风险，但动力是一个问题。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。公共健康相关性：GRK4 基因的变体预测血压会随着盐摄入量的增加而升高，准确率达 70-90%。对于携带该基因变异的个体来说，利尿剂可以更有效地降低血压。这些研究的结果将有益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。