Cytosolic Phospholipase A2 in Cardiac Hypertrophy

描述（由申请人提供）：充血性心力衰竭是导致死亡和残疾的主要原因，通常在此之前有一段以心脏肥厚生长为特征的时期。相对而言，我们对脂质介质在这一反应中的作用知之甚少。基于对小鼠基因编码缺失的研究，我们认为cPLA2可以调节正常生长和病理性应激诱导的心脏肥厚生长。cPLA2是一种关键的酶，在许多刺激下控制AA的释放。我们认为cPLA2作用的产物调节了控制许多物种生长的基本途径- IGF- 1途径。我们的主要假设是：1)cPLA2产物通过增强IGF- 1受体/IRS-i复合物的负调节因子的募集来下调IGF- 1信号。在cpla2缺陷小鼠中，未能招募这种负调节因子导致igf - 1信号的激活增强；2) IGF-1信号的失调调节导致该通路下的信号传递增强，这是导致cpla2缺陷小鼠心脏生理性和病理性生长夸大的原因。我们将在四个具体目标中评估这些假设：1。确定cPLA2调控igf - 1信号传导的机制。我们将确定IGF-1信号的负调节因子，以及负责将其招募到IGF-1RJIRS-1复合体的脂质介质（即cPLA2产物）。2. 确定cPLA2调控心肌肥厚的机制。我们将在来自cpla2缺陷小鼠的心肌细胞中研究这些机制。3. 确定cPLA2在体内正常心脏生长中的作用。我们认为cPLA2对igf - 1信号的负调控是心脏正常生长的重要“刹车”。这些研究将确定cPLA2调节IGF- I信号对心脏生长的生理重要性。4. 确定cPLA在病理性应激诱导的体内肥厚生长中的作用。我们将定义cPLA2在两种人类心血管疾病模型中的作用——压力超载和心肌梗死后重构。我们的数据首次表明cPLA2参与IGF- 1信号的负调控，以及心脏正常生长和肥厚生长的负调控。拟议的研究应确定IGF- 1通路调节的新分子机制，并为心肌肥厚发生和进展的基本机制提供重要见解。

DESCRIPTION (provided by applicant): Congestive heart failure is a leading cause of death and disability, and is usually preceded by a period characterized by hypertrophic growth of the heart. Relatively little is known about the role of lipid mediators in the response. Based on studies with a mouse deleted for the gene encoding cytosolic phospholipase A2 (cPLA2) which is a critical enzyme controlling the release of AA in response to many stimuli, we believe that cPLA2 regulates normal growth and pathologic stress-induced hypertrophic growth of the heart. We believe that a product of cPLA2 action regulates a basic and fundamental pathway that controls growth across many species- the IGF- 1 pathway. Our overriding hypotheses are: 1) a cPLA2 product down-regulates IGF- 1 signaling by enhancing the recruitment of a negative regulator to the IGF- 1 receptor/IRS-i complex. The failure to recruit this negative regulator leads to the enhanced activation of IGF-l signaling in the cPLA2-deficient mouse; and 2) the disordered regulation of IGF-1 signaling leads to enhanced signal transmission down the pathway, and this is the cause of the exaggerated physiologic and pathologic growth of the heart of the cPLA2-deficient mouse. We will evaluate these hypotheses in four Specific Aims: 1. Determine the mechanism by which cPLA2 regulates IGF-l signaling. We will identify the negative regulator of IGF-1 signaling, and the lipid mediator (i.e. cPLA2 product) responsible for its recruitment to the IGF-1RJIRS-1 complex. 2. Determine the mechanism by which cPLA2 regulates cardiomvocvte hvpertrophv. We will examine these mechanisms in cardiomyocytes derived from the cPLA2-deficient mouse. 3. Determine the role of cPLA2 in normal cardiac growth in vivo. We believe that the negative regulation of IGF-l signaling by cPLA2 is an important "brake" on normal cardiac growth. These studies will determine the physiologic importance of the regulation of IGF- I signaling by cPLA2 on cardiac growth. 4. Determine the role of cPLA, in pathologic stress-induced hvpertrophic growth in vivo. We will define the role of cPLA2 in two models of human cardiovascular disease- pressure overload and post-myocardial infarction remodeling.Our data are the first to implicate cPLA2 in the negative regulation of IGF- 1 signaling and in the negative regulation of normal growth and of hypertrophic growth of the heart. The proposed studies should identify novel molecular mechanisms by which the IGF- 1 pathway is regulated and should provide important insights into the basic mechansims underlying the development and progression of cardiac hypertrophy.