As a result of recent advances in our understanding of cardiac muscle signaling pathways for cardiac growth and hypertrophy, coupled with recent advances in the development of molecular physiology in transgenic mice, the molecular dissection of the pathways which lead to cardiac muscle dysfunction appears to be feasible. Accordingly , the central objective of the present project is to critically examine the pathological role of a subset of candidate genes which have been implicated in the transition between compensatory hypertrophy to cardiac muscle dysfunction. This approach is based upon the recent identification of a number of candidate signaling molecules that have been implicated in wither cardiac hypertrophy and/or in cardiac muscle dysfunction). Dominantly active (positive or negative) forms of these proteins will be expressed in the ventricular chamber by fusing the corresponding cDNAS to a 250 bp MLC-2 promoter fragment that will confer ventricular-specific expression in transgenic mice. The physiological phenotypes can then be analyzed via miniaturized technology that has been pioneered at UCSD. Accordingly, the specific aims of the present proposal are as follows: 1) To examine the role of insulin-like growth factor-1 (IGF-1) in the transition between compensatory hypertrophy and cardiac muscle dysfunction in transgenic mice. 2) To examine the role of Ras and Gq dependent signaling pathways in the onset of cardiac hypertrophy, dysfunction, and failure in transgenic mice. 3) To examine the effects of beta-myosin heavy chain missense mutations in the onset of cardiac dysfunction and failure in transgenic mice. 4) To examine the combinatorial effects of the interaction of these and other genes on cardiac muscle hypertrophy and failure through mating into various genetic backgrounds. The development of genetic-based models of cardiac muscle failure will allow the implementation of mouse genetics to identify genes which act together to activate the cardiac failure phenotype and/or genes that might repress the pathological response through mating into other genetic backgrounds. Also, insights from other model systems, which are garnered in other sections of this SCOR Program, can be readily integrated into this Project to develop alternative genetic models in transgenic mice, or to monitor the cardiac muscle cell phenotype in the various transgenic lines.
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