GRK4 and development of salt sensitivity (R01HL092196)

GRK4 和盐敏感性的发展 (R01HL092196)

• 批准号: 8659817
• 负责人: Ines Armando
• 金额: $ 38.38万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659817
• 关键词: 4p16.3; Angiotensins; Blood Pressure; Caucasians; Caucasoid Race; Cells; Chinese People; Data; Defect; Development; Dopamine; Dopamine D1 Receptor; Drug Targeting; Electrolyte Balance; Equilibrium; Essential Hypertension; Ethnic group; Excretory function; Fluid Balance; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GRK4 gene; Genes; Genetic; Human; Hypertension; Inbred SHR Rats; Intake; Japanese Population; Kidney; Lead; Limb structure; Link; Mediating; Molecular; Morbidity - disease rate; Mus; Nephrons; Normal Range; Orphan; Pathogenesis; Population; Promoter Regions; Proximal Kidney Tubules; Rattus; Receptor, Angiotensin, Type 1; Regulation; Resistance; Rodent; Role; SJL/J Mouse; Second Messenger Systems; Sodium; Sodium Chloride; System; Testing; Thick; Time; Transgenes; Variant; blood pressure regulation; cardiovascular risk factor; desensitization; genetic strain; genetic variant; glucocorticoid-induced orphan receptor; mRNA Expression; mortality; normotensive; novel; paracrine; protective effect; public health relevance; receptor expression; receptor function; response; salt sensitive; saluretic; second messenger

DESCRIPTION (provided by applicant): The genetic causes of salt sensitivity in humans are not well known. The kidney is critical to the overall fluid and electrolyte balance and long-term regulation of blood pressure (BP). Therefore, the pathogenesis of salt sensitivity must involve an inability to decrease sodium transport and increase sodium excretion when the sodium load is increased. Variants of the human G protein-coupled receptor kinase type 4 (hGRK) genes that regulates a limited number of G protein-coupled receptors, are associated with essential hypertension in several ethnic groups. Expression of the hGRK4g486V variant in mice causes salt sensitivity depending on the genetic background. Preliminary data suggest that the orphan receptor GPR83 may counteract the salt- sensitive producing effect of hGRK4g 486V, the expression of which is dependent on the genetic background and may explain ethnic-related differences in salt sensitivity. This project will test the overall novel hypothesis that salt sensitivity imparted by hGRK4g 486V is due to decreased expression/function of the orphan receptor GPR83 that results in an imbalance in natriuretic (dopamine D1 receptor, D1R) and antinatriuretic (angiotensin type 1 receptor, AT1R) systems which increases BP. Specific Aim 1 will test the hypothesis that GPR83 function is necessary to maintain a normal blood pressure under conditions of sodium excess and that lack or decreased GPR83 function will have the least effect on mice in a salt-resistant background. This Specific Aim 1 will also clarify the effects of GRK4 and D1R on the regulation of GPR83 expression. Specific Aim 2 will test the hypothesis that the protective effects of GPR83 are mediated by negative regulation of AT1R and positive regulation of D1R functions. This Specific Aim will clarify the cellular mechanisms involved in the regulation of these functions. Specific Aim 3 will test the hypothesis that GPR83 function is impaired by hGRK4g486V and that the ability to impair GPR83 function is dependent on the proportion of "salt sensitivity" and "salt resistance" genes. In mice with a predominant salt-sensitive background renal GPR83 is necessary to maintain normal blood pressure even when sodium intake is not increased. These studies will be able to determine, for the first time, the role of the interaction of "salt sensitivity" and "salt resistance" genes in the pathogenesis o essential hypertension. The identification of a novel salt resistance gene, i.e., GPR83, may lead to the development of drugs that target its expression and function.

描述(申请人提供)：人类对盐敏感的遗传原因还不是很清楚。肾脏对整体体液和电解质的平衡以及长期调节血压(BP)至关重要。因此，盐敏感性的发病机制必然涉及当钠负荷增加时不能减少钠转运和增加钠排泄。人类G蛋白偶联受体激酶4(HGRK)基因的变异调节有限数量的G蛋白偶联受体，在几个民族中与原发性高血压有关。在小鼠中表达hGRK4g486V变体会导致盐敏感性，这取决于遗传背景。初步数据表明，孤儿受体GPR83可能抵消hGRK4G 486V对盐敏感的产生效应，其表达依赖于遗传背景，并可能解释与种族相关的盐敏感性差异。这个项目将测试整个新的假设，即hGRK4G 486V赋予的盐敏感性是由于孤儿受体GPR83的表达/功能降低，导致钠尿剂(多巴胺D1受体，D1R)和抗心钠剂(血管紧张素1型受体，AT1R)系统失衡，从而增加血压。具体目标1将测试一种假设，即在钠过量的条件下，GPR83功能是维持正常血压所必需的，而缺乏或降低GPR83功能对耐盐背景下的小鼠的影响最小。这一特定目的1还将阐明GRK4和D1R在GPR83表达调控中的作用。特定目的2将验证GPR83的保护作用是通过AT1R的负调节和D1R功能的正调节而介导的假说。这一特定的目的将阐明参与这些功能调节的细胞机制。特异靶3将验证GPR83功能被hGRK4g486V损害的假设，以及损害GPR83功能的能力取决于“盐敏感”和“抗盐”基因的比例。在具有主要盐敏感背景的小鼠中，即使在钠摄入量没有增加的情况下，肾脏GPR83也是维持正常血压所必需的。这些研究将首次确定“盐敏感”和“耐盐”基因在高血压发病机制中的作用。一个新的抗盐基因GPR83的发现可能会导致针对其表达和功能的药物的开发。