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.
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