RGS PROTEIN FUNCTION IN CARDIAC PHYSIOLOGY

RGS 蛋白在心脏生理学中的功能

基本信息

批准号：
6390130
负责人：
ANTHONY JUSTIN MUSLIN
金额：
$ 23.6万
依托单位：
BARNES-JEWISH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-15 至 2004-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6390130
关键词：
biological signal transduction cardiac myocytes cell growth regulation cell morphology congestive heart failure disease /disorder model gene mutation guanosinetriphosphatase activating protein heart function human tissue laboratory mouse laboratory rat newborn animals tissue /cell culture ventricular hypertrophy

项目摘要

Postnatal mammalian cardiomyocytes respond to mechanical stress, growth factor and hormonal action, and metabolic abnormalities by enlarging, but these cells are unable to proliferate for reasons that are not understood. The clinical consequences of human cardiac hypertrophy are very significant and include the development of serious cardiac arrhythmias, of diastolic dysfunction that can result in pulmonary edema and fluid overload, and of congestive heart failure. Intracellular signaling cascades play a major role in the development of cardiac hypertrophy. Several lines of evidence support the role of G proteins in the development of cardiac hypertrophy. RGS (regulator of G protein signaling) proteins were recently found to be GTPase activating proteins (GAPs) for heterotrimeric G proteins. In this proposal, we will outline experiments to test the hypothesis that RGS proteins determine the responsiveness of cardiomyocytes to extracellular stimuli, and that RGS gene expression can be increased as an adaptive mechanism to limit G- protein-mediated signal transduction. We will examine the expression pattern of RGS family members in animal models of cardiac hypertrophy and congestive heart failure. We will determine the relative ability of RGS family members to block cardiomyocyte signal transduction and hypertrophic growth. We will determine whether RGS4 inhibits cardiac hypertrophy in a transgenic mouse model in response to provocative stimuli. Finally, we will determine whether dominant negative mutant forms of RGS2 and RGS4 promote cardiomyocyte signal transduction and hypertrophic growth. These experiments will help to establish the role of RGS proteins in the pathophysiology of cardiac hypertrophy and may have an impact on future treatment of patients with this disorder and those in whom hypertrophy has progressed to heart failure.

出生后的哺乳动物心肌细胞通过增大来应对机械应力、生长因子和激素作用以及代谢异常，但这些细胞无法增殖，原因尚不清楚。人类心脏肥大的临床后果非常严重，包括严重心律失常、可导致肺水肿和液体超负荷的舒张功能障碍以及充血性心力衰竭的发生。细胞内信号级联在心脏肥大的发展中起着重要作用。多项证据支持 G 蛋白在心脏肥大发展中的作用。最近发现 RGS（G 蛋白信号传导调节蛋白）蛋白是异源三聚体 G 蛋白的 GTP 酶激活蛋白 (GAP)。在本提案中，我们将概述实验来检验以下假设：RGS 蛋白决定心肌细胞对细胞外刺激的反应性，并且 RGS 基因表达可以作为限制 G 蛋白介导的信号转导的适应性机制而增加。我们将检查 RGS 家族成员在心脏肥大和充血性心力衰竭动物模型中的表达模式。我们将确定 RGS 家族成员阻断心肌细胞信号转导和肥大生长的相对能力。我们将确定 RGS4 是否会抑制转基因小鼠模型响应刺激的心脏肥大。最后，我们将确定 RGS2 和 RGS4 的显性失活突变形式是否促进心肌细胞信号转导和肥大生长。这些实验将有助于确定 RGS 蛋白在心脏肥大病理生理学中的作用，并可能对患有这种疾病的患者和肥厚已进展为心力衰竭的患者的未来治疗产生影响。