GRK4 and development of salt sensitivity
GRK4 与盐敏感性的发展
基本信息
- 批准号:8266339
- 负责人:
- 金额:$ 37.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:4p16.3AccountingAdenylate CyclaseAdolescentAdultAfricanAfrican AmericanAgeAwardBehavior TherapyBlood PressureBudgetsC57BL/6 MouseCardiovascular systemCaucasiansCaucasoid RaceCellsChildChinese Hamster Ovary CellChinese PeopleComplexCongressesDevelopmentDiagnostic testsDietary SodiumDiseaseDiureticsDopamineDopamine D1 ReceptorDopamine ReceptorDrug FormulationsElectrolytesEmbryoEssential HypertensionEthnic groupExcretory functionFigs - dietaryG protein coupled receptor kinaseG protein-coupled receptor kinase 4G-Protein-Coupled ReceptorsGTP-Binding ProteinsGenesGeneticGenetic VariationHealthHeartHomeostasisHumanHuman ChromosomesHypertensionHypotensionInbred C57BL MiceIndividualIntakeJapanese PopulationKidneyKnock-outLaboratoriesLegal patentLife StyleLinkMorbidity - disease rateMotivationMusNational Heart, Lung, and Blood InstitutePathogenesisPharmacogenomicsPharmacotherapyPhenotypeProtein IsoformsProximal Kidney TubulesPsyche structureRegulationReportingResearchResistanceRoleSJL MouseSJL/J MouseSodiumSodium ChlorideStressSturnus vulgarisTestingTransgenic MiceTransgenic OrganismsTubular formationVariantWaterWorkcardiovascular risk factorcaucasian Americangene replacementhuman subjectlecturesmortalitynormotensiveoverexpressionpreventreceptor functionsalt intakesalt sensitivesaluretic
项目摘要
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):与血压无关的高钠摄入量与心血管风险增加有关。然而,盐敏感的遗传原因(S)尚不清楚。将基因与高血压和盐敏感等复杂疾病联系起来的确凿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)是唯一符合这一标准的高血压致病基因,即GRK4基因变异可引起小鼠的盐敏感性和高血压。GRK43 142V转基因小鼠发生了耐盐性高血压,而GRK43 486V转基因小鼠出现了盐敏感型高血压。根据遗传背景的不同,GRK43野生型的过表达使盐敏感小鼠(C57BL/6J)转变为耐盐小鼠,而GRK43 486V过表达则使耐盐小鼠(SJL/J)转变为盐敏感小鼠。总体目标是验证人类GRK43野生型赋予盐抗性,而人类GRK43486V导致盐敏感型高血压的假设。目的1验证人类GRK43野生型通过促进钠的排泄而引起耐盐性的假说。这种表型的改变部分是由于人类GRK43野生型对GPCRs(如D1R和AT1R)的差异调节,参与控制肾脏的盐运输和血压。目的2验证人类GRK43486V导致盐敏感型高血压的假说,部分是通过损害肾脏D1R功能和增强AT1R表达。我们将研究GRK4基因敲除和人GRK43野生型基因及其变异体(486V)对小鼠肾脏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、青少年和成人盐摄入量的适度减少会立即导致血压下降,并带来长期的好处。然而,饮食中的钠限制并不是对所有人都有利。生活方式会改变血压,降低心血管风险,但动机是个问题。这些研究的结果可能对制定诊断测试、药物治疗(药物基因组学)和改变生活方式很重要。与公共健康相关:一种名为GRK4的基因的变异预测血压将随着盐摄入量的增加而上升,准确率为70%-90%。在携带该基因变异的个体中,利尿剂对降低血压更有效。这些研究的结果将有助于诊断测试的制定,以及药物治疗(药物基因组学)和生活方式的改变。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Pedro A. Jose其他文献
Role of AT1 receptor Ubiquitination in the D5 dopamine receptor‐mediated AT1 receptor degradation
AT1 受体泛素化在 D5 多巴胺受体介导的 AT1 受体降解中的作用
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:0
- 作者:
Hewang Li;P. Yu;Pedro A. Jose - 通讯作者:
Pedro A. Jose
Role of renal DJ-1 in the regulation of Nrf2 and oxidative stress-mediated hypertension
- DOI:
10.1016/j.jash.2014.03.240 - 发表时间:
2014-04-01 - 期刊:
- 影响因子:
- 作者:
Santiago Cuevas;Yu Yang;Laureamo Asico;Jun Feranil;Prasad Konkalmatt;Ines Armando;Pedro A. Jose - 通讯作者:
Pedro A. Jose
The ontogeny of the renin-angiotensin system.
肾素-血管紧张素系统的个体发育。
- DOI:
10.1016/s0095-5108(18)31085-6 - 发表时间:
1981 - 期刊:
- 影响因子:2.1
- 作者:
Juan C. Pelayo;G. Eisner;Pedro A. Jose - 通讯作者:
Pedro A. Jose
Long-term exposure of PM2.5 causes hypertension by impaired renal D1 receptor mediated sodium excretion via up-regulation of GRK4 expression in SD rats
长期暴露于 PM2.5,SD 大鼠肾 D1 受体受损,上调 GRK4 表达,介导钠排泄,从而导致高血压
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Xi Lu;Zhengmeng Ye;Shuo Zheng;Hongmei Ren;Jing Zeng;Xinquan Wang;Pedro A. Jose;Ken Chen;Chunyu Zeng - 通讯作者:
Chunyu Zeng
Position paper on current status and future needs of pediatric nephrology in the United States: Training and research
- DOI:
10.1007/bf00858549 - 发表时间:
1989-09-01 - 期刊:
- 影响因子:2.600
- 作者:
Russell W. Chesney;Billy S. Arant;Gladys Hirschmann;Pedro A. Jose;Antonia C. Novello;Norman J. Siegel - 通讯作者:
Norman J. Siegel
Pedro A. Jose的其他文献
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{{ truncateString('Pedro A. Jose', 18)}}的其他基金
Lipid rafts, dopamine 1 receptor, and hypertension
脂筏、多巴胺 1 受体和高血压
- 批准号:
9886774 - 财政年份:2020
- 资助金额:
$ 37.99万 - 项目类别:
Lipid rafts, dopamine 1 receptor, and hypertension
脂筏、多巴胺 1 受体和高血压
- 批准号:
10544330 - 财政年份:2020
- 资助金额:
$ 37.99万 - 项目类别:
Lipid rafts, dopamine 1 receptor, and hypertension
脂筏、多巴胺 1 受体和高血压
- 批准号:
10083735 - 财政年份:2020
- 资助金额:
$ 37.99万 - 项目类别:
Lipid rafts, dopamine 1 receptor, and hypertension
脂筏、多巴胺 1 受体和高血压
- 批准号:
10319571 - 财政年份:2020
- 资助金额:
$ 37.99万 - 项目类别:
Ds receptor antioxidant activity and hypertension
Ds受体抗氧化活性与高血压
- 批准号:
8148031 - 财政年份:2010
- 资助金额:
$ 37.99万 - 项目类别:
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