In recent years progress has been made in the understanding of the signal transduction mechanisms which regulate cell growth in a variety of cell types. Cardiac muscle cells are a particularly interesting and important system in which to study the regulation of growth. During embryonic development differentiated cardiac myocytes divide. Around about the time of birth, the cells lose the capacity to proliferate and from this time on growth of the heart occurs through a process of cellular hypertrophy where each cell gets bigger. Excessive hypertrophic growth is associated with impaired cardiac function and is an important disease problem in our society. The mechanisms which regulate these processes are poorly understood. This proposal aims to further our understanding of the regulation of cardiac cell growth by analyzing signal transduction pathways leading to cardiac cell hypertrophy and proliferation. In particular, we wish to test the hypothesis that cardiac cell growth and hypertrophy arise from the activation of signaling pathways that use molecules (Ras, MAP kinase, Raf, GAP, p190 and Rho) which have been implicated in the regulation of growth and differentiation of other cell types. This will be achieved by analyzing the effects of wildtype and mutant (activated and inhibitory) signaling molecules on gene expression and morphological changes associated with cardiac cell hypertrophy. Complementary experiments using specific antibodies to inhibit cellular activities and analysis of the biochemical activity of the signaling molecules after stimulation with agonists which induce hypertrophy will also be performed. In addition, we will carry out experiments designed to investigate the roles of these proteins in the regulation of proliferation of embryonic myocytes. Taken together these experiments should allow us to compare the molecular mechanisms which regulate both proliferative and non-proliferative (hypertrophic) growth. Analysis of the signaling mechanisms through which cardiac cell growth and hypertrophy are regulated will enable us to better understood what happens during cardiac disease. In the long term, understanding these processes in molecular terms may allow us to intervene in a rational way to prevent progression of disease states. This work will provide a means to analyze the interactions between various signaling molecules leading to different phenotypes. This work may therefore be generally relevant for our understanding of the ways in which different end results are produced from the activation of a particular signal transduction pathway.
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