CELLULAR AND MOLECULAR MECHANISMS UNDERLYING HEART FAILURE: G PROTEIN AQ SUBUNIT

心力衰竭的细胞和分子机制：G 蛋白 AQ 亚基

基本信息

批准号：
6564945
负责人：
EVA J. NEER
金额：
$ 21.47万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2003-01-31
项目状态：
已结题

项目摘要

Receptors for many cardiac hormones and neurotransmitters are coupled to their effector enzymes and ion channels by a family of heterotrimeric GDP-binding proteins (G proteins made up of alpha and betagamma subunits. These proteins act as critical control points for directing signals initiated at the cell surface to specific intracellular second messenger pathways. They are essential for normal cardiac function, and their derangement in pathological states may contribute to abnormal responses of the heart to some agonists. In the past project period, we have created strains of transgenic mice carrying mutated G protein subunits targeted to the heart. One set of animals expressing a constitutively activated, HA epitope-tagged Galpha subunit (HAalpha/q*) develops cardiac hypertrophy, dilation and failure. Surprisingly, we found that expression of HAalpha/q* was transient, being present at 2 weeks in atria and ventricles, and becoming undetectable by 10 weeks of age. At 2 weeks of age when the product of the transgene is expressed, the hearts are essentially normal morphologically, but not functionally. This early transient expression of HAALPHA/q* causes pathological changes that continue and that worsen despite the fact that the level of HAalpha/q* drops. These mice provide a powerful, novel system in which to dissect primary from secondary changes leading to cardiac hypertrophy and eventually to failure. A major challenge is to define how changes that begin in the cardiomyocyte lead to changes in non-myocyte cells to produce the full-blown global cardiac pathology. Ultimately, the persistent pathology must be the result of persistent changes in the activity of sets of genes. A major long-term goal will be to use the system that we have developed to identify novel genes involved in the initiation and continuation of cardiac dilatation hypertrophy and the transition to failure, and to understand how changes in their function determine the pathology. Ultimately, the persistent pathology must be the result of persistent changes in the activity of sets of genes. A major long-term goal will be to use the system that we have developed to identify novel genes involved in the initiation and continuation of cardiac dilatation hypertrophy and the transition to failure, and to understand how changes in their function determine the pathology. The Specific Aims are: 1) To define the mechanisms that link transient expression of constitutively activated alpha/1 in cardiac myocytes to persistent, fatal cardiac pathology. 2) To define the change in gene expression profile in cardiomyocytes from transgenic animals expressing HAalpha1* at an age when pathology is minimal and when it is severe. Transgenic animals will also be compared to age- and sex-matched wild-type animals. 3) To define the effect of increased alpha/1 signaling on development of hypertrophy through an independent pathway.

许多心脏激素和神经递质的受体通过异三聚体 GDP 结合蛋白家族（由 α 和 βamma 亚基组成的 G 蛋白）与其效应酶和离子通道偶联。这些蛋白质充当引导细胞启动信号的关键控制点它们对于正常的心脏功能至关重要，并且它们在病理状态下的紊乱可能导致心脏对某些激动剂的异常反应。我们创建了携带针对心脏的突变 G 蛋白亚基的转基因小鼠品系，一组表达组成型激活的 HA 表位标记的 Galpha 亚基 (HAalpha/q*) 的动物出现了心脏肥大、扩张和衰竭。 HAalpha/q* 的表达是短暂的，在 2 周龄时出现在心房和心室中，并在 10 周龄时变得不可检测。当转基因产物表达后，心脏在形态上基本正常，但在功能上不正常。尽管 HAalpha/q* 水平下降，但 HAALPHA/q* 的这种早期短暂表达会导致病理变化持续并恶化。这些小鼠提供了一个强大的新颖系统，可以将原发性变化与导致心脏肥大并最终导致衰竭的继发性变化分开。一个主要的挑战是定义心肌细胞中开始的变化如何导致非心肌细胞的变化，从而产生全面的整体心脏病理学。最终，持续的病理必然是基因组活性持续变化的结果。一个主要的长期目标是利用我们开发的系统来识别参与心脏扩张肥大的启动和持续以及向衰竭转变的新基因，并了解它们的功能变化如何决定病理学。最终，持续的病理必然是基因组活性持续变化的结果。一个主要的长期目标是利用我们开发的系统来识别参与心脏扩张肥大的启动和持续以及向衰竭转变的新基因，并了解它们的功能变化如何决定病理学。具体目标是： 1) 明确心肌细胞中组成型激活的 α/1 的瞬时表达与持续性致命心脏病理学之间的联系机制。 2) 确定表达HAalpha1*的转基因动物在病理最轻微和严重时的心肌细胞中基因表达谱的变化。转基因动物还将与年龄和性别匹配的野生型动物进行比较。 3) 通过独立途径确定增加的 alpha/1 信号传导对肥大发展的影响。