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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6564945
• 关键词: G protein; adenylate cyclase; age difference; antisense nucleic acid; biological signal transduction; cardiac myocytes; disease /disorder model; gene expression; gene mutation; genetic models; genetically modified animals; heart failure; heart function; idiopathic dilated cardiomyopathy; laboratory mouse; molecular pathology; protein structure function; tissue /cell culture; ventricular hypertrophy

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.

许多心激素和神经递质的受体通过一个异三聚体GDP结合蛋白（由α和β蛋白组成的G蛋白和β蛋白组成的G蛋白与这些蛋白质成立的蛋白质的关键控制点，指导他们在Cell Surfaction Pathient function sissile controctional sissergers sissergers sissergeends sissergeend sissergeend sisssive sisssive ssissergersssiveers sissergeend coptssign sissergersssiveends sissergers sissergeend蛋白（g蛋白）。病态状态的危险可能导致对某些激动剂的异常反应，在过去的项目时期，我们的转基因小鼠携带了突变的G蛋白亚基，这些小鼠靶向一组对心脏的动物。 Haalpha/Q*是短暂的，在心室和心室中存在2周，并且在表达转基因的乘积时，在10周大的时候就无法检测到。 Haalpha/Q*的这种早期瞬态表达会导致病理变化，尽管Haalpha/Q*的水平下降了，但仍会持续并恶化。这些小鼠提供了一个强大的新型系统，可以在其中从导致心脏肥大并最终导致失败的次要变化中剖析主要变化。一个主要的挑战是定义在心肌细胞中开始的变化如何导致非肌细胞细胞的变化以产生全球的全球心脏病理。最终，持续的病理必须是基因集活动持续变化的结果。一个主要的长期目标是使用我们开发的系统来识别与心脏扩张肥大的启动和延续有关的新基因，并过渡到失败，并了解其功能的变化如何确定病理。最终，持续的病理必须是基因集活动持续变化的结果。一个主要的长期目标是使用我们开发的系统来识别与心脏扩张肥大的启动和延续有关的新基因，并过渡到失败，并了解其功能的变化如何确定病理。具体目的是：1）定义将心肌细胞中组成型激活的α/1瞬时表达连接到持续性致命心脏病理学的机制。 2）定义从表达Haalpha1*的转基因动物的心肌细胞中基因表达谱的变化，而病理学最小并且何时严重。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）定义增加α/1信号通过独立途径发展肥大的影响。