GRK4 and development of salt sensitivity

GRK4 与盐敏感性的发展

• 批准号: 8266339
• 负责人: Pedro A. Jose
• 金额: $ 37.99万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266339
• 关键词: 4p16.3; Accounting; Adenylate Cyclase; Adolescent; Adult; African; African American; Age; Award; Behavior Therapy; Blood Pressure; Budgets; C57BL/6 Mouse; Cardiovascular system; Caucasians; Caucasoid Race; Cells; Child; Chinese Hamster Ovary Cell; Chinese People; Complex; Congresses; Development; Diagnostic tests; Dietary Sodium; Disease; Diuretics; Dopamine; 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; Health; 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; Pathogenesis; Pharmacogenomics; Pharmacotherapy; Phenotype; Protein Isoforms; Proximal Kidney Tubules; Psyche structure; Regulation; Reporting; Research; Resistance; Role; SJL Mouse; SJL/J Mouse; Sodium; Sodium Chloride; Stress; Sturnus vulgaris; Testing; Transgenic Mice; Transgenic Organisms; Tubular formation; Variant; Water; Work; cardiovascular risk factor; caucasian American; gene replacement; human subject; lectures; mortality; normotensive; overexpression; prevent; 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，与心血管风险增加有关。然而，尚不清楚盐敏感性的遗传原因。将基因与复杂疾病联系起来的明确证据，例如高血压和盐敏感性，是将一种表型交换为另一种表型。 G蛋白偶联受体激酶4（GRK4）是唯一认为满足该标准的高血压因果的基因，即GRK4基因变体在小鼠中产生盐敏感性和高血压。 GRK43 142V转基因小鼠会产生耐盐的高血压，而GRK43 486V转基因小鼠会产生盐敏感的高血压。根据遗传背景，GRK43野生型的过表达将盐敏感小鼠（C57BL/6J）转换为耐盐小鼠，而GRK43 486V的过表达将耐盐小鼠（SJL/J）转换为盐敏感小鼠。总体目的是检验以下假设：人类GRK43野生型会赋予盐耐药性，而人类GRK43 486V会导致盐敏感的高血压。 AIM 1将检验以下假设：人类GRK43野生型通过促进钠排泄来引起盐的耐药性。表型的这种变化部分归因于人类GRK43野生型差异调节GPCR（例如D1R和AT1R）涉及肾脏NaCl转运和血压的控制。 AIM 2将检验以下假设：人类GRK43 486V会通过损害肾脏D1R功能并增强AT1R表达而导致盐敏感的高血压。将研究将研究小鼠中的GRK4敲除和靶向基因替代的靶向基因（486V）对肾脏钠排泄和血压调节的影响。这些研究将使盐敏感性机理及其对血压的影响进行解密。儿童，青少年和成年人的盐摄入量的适度降低导致血压立即降低，并具有长期的益处。但是，饮食中的钠限制可能对所有人都不是有益的。生活方式会改变降低血压并降低心血管风险，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）和生活方式修饰可能很重要。公共卫生相关性：一个名为GRK4的基因的变体预测，精度为70-90％，血压将随着盐摄入量增加而升高。利尿剂在降低该基因变异的个体的血压方面更有效。这些研究的结果将有助于制定诊断测试，药物治疗（药物基因组学）和生活方式修饰。