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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL067371-01A2
Application #
6544396
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Liang, Isabella Y
Project Start
2002-07-25
Project End
2006-06-30
Budget Start
2002-07-25
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$404,375
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
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