RGS Protein Function in Cardiac Physiology

RGS 蛋白在心脏生理学中的功能

• 批准号: 6917674
• 负责人: ANTHONY JUSTIN MUSLIN
• 金额: $ 34.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917674
• 关键词: biological signal transduction; blood pressure; cardiac myocytes; cardiovascular disorder epidemiology; cell growth regulation; disease /disorder model; exercise; gene deletion mutation; gene expression; gene targeting; genetically modified animals; guanosinetriphosphatase activating protein; heart contraction; heart disorder; heart function; laboratory mouse; laboratory rat; newborn animals; pathologic process; protein structure function; tissue /cell culture; ventricular hypertrophy

DESCRIPTION (provided by applicant): Cardiac hypertrophy in humans is frequently associated with a poor prognosis. In cultured rat cardiac myocytes, ligands such as phenylephrine, endothelin-1, angiotensin II, and prostaglandin F2alpha promote a hypertrophic response. There is evidence that the action of these ligands on cultured cells mimics cardiac hypertrophy in humans. Most agonists that cause cultured cardiomyocytes to hypertrophy signal via heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins are GTPase activating proteins (GAPs) that deactivate asubunits of heterotrimeric G proteins. The main aim of this proposal is to investigate the physiologic role of RGS proteins in the regulation of cardiac hypertrophic growth program. The central hypothesis is that RGS proteins determine the responsiveness of cardiac myocytes to extracellular stimuli, and that RGS gene expression is increased as an adaptive mechanism to limit Gprotein- mediated signal transduction. In the original funding period, we demonstrated that RGS proteins are present in heart, that RGS3 and RGS4 gene expression is responsive to external stimuli, that cardiacspecific overexpression of RGS4 in mice blocks pressure overload- and exercise-induced cardiac hypertrophy, and that RGS4 is a GAP for Gq in the in vivo heart. Despite these findings, many questions remain about the role of RGS proteins in heart disease. In the next phase of this project, we propose to investigate the specific role of RGS2, RGS3, and RGS4, in cardiac myocyte hypertrophy by use of a "knock-down" strategy in cultured cells. Second, we investigate the specific role of RGS4 in pressure overload- and exercise-induced cardiac hypertrophy by use of mice with both whole-body and cardiacspecific targeted disruption of this gene. Third, we investigate the specific role of RGS3 in pressure overload- and exercise-induced cardiac hypertrophy by use of mice with whole-body targeted disruption of this gene. These experiments will help define the role of RGS proteins in the pathogenesis of cardiac hypertrophy and contractile dysfunction and may provide important information for the development of novel therapeutic agents.

描述（由申请人提供）：人类心脏肥大经常与预后不良有关。在培养的大鼠心肌细胞中，苯肾上腺素，内皮素-1，血管紧张素II和前列腺素F2alpha等配体促进了肥大反应。有证据表明，这些配体对培养细胞的作用模仿了人类的心脏肥大。大多数通过异三聚体G蛋白引起肥大信号的培养心肌细胞的激动剂。 G蛋白信号传导（RGS）蛋白的调节剂是GTPase激活蛋白（GAPS），可将杂物二聚体G蛋白的抗育蛋白失效。该提案的主要目的是研究RGS蛋白在心脏肥大生长计划调节中的生理作用。中心假设是RGS蛋白决定了心肌细胞对细胞外刺激的反应性，并且RGS基因表达被增加作为限制Gprotein介导的信号转导的一种适应性机制。在最初的资金期间，我们证明了RGS蛋白质存在于心脏中，RGS3和RGS4基因表达对外部刺激有反应，RGS4的心脏特异性过表达会阻止压力超负荷和运动诱导的心脏肥大，并且RGS4对于GQ中的GQ是Vivo Heart in In vivo Heart in In vivo Heart in In vivo Heart a Heart in In vivo Heart a Heart in In vivo。尽管有这些发现，但关于RGS蛋白在心脏病中的作用仍然存在许多问题。在该项目的下一个阶段，我们建议通过在培养细胞中使用“敲低”策略来研究心肌肥大中RGS2，RGS3和RGS4的特定作用。其次，我们通过使用具有全身和心脏特异性靶向靶向破坏的小鼠，研究了RGS4在压力过载和运动诱导的心脏肥大中的特定作用。第三，我们通过使用该基因的全身靶向破坏的小鼠，研究了RGS3在压力超负荷和运动诱导的心肥大中的特定作用。这些实验将有助于定义RGS蛋白在心脏肥大和收缩功能障碍的发病机理中的作用，并可能为开发新型治疗剂提供重要信息。