The theme of this application is to characterize reactive intracellular signaling pathways that promote cardiac hypertrophy. In response to various disease states the myocardium undergoes hypertrophic growth as a means of compensation. This compensation eventually leads to greater pathology and progressive deterioration of function. An understanding of the intracellular signaling pathways that cause or regulate hypertrophic growth of the heart will permit development of new therapies for certain forms of heart disease. The laboratory has recently identified a novel calcium responsive intracellular signaling pathway that likely plays an important role in regulating cardiac hypertrophy. It was shown that the calcium regulated phosphatase calcineurin (PP2B) and the downstream transcription factor NFAT3 are key components of cardiomyocyte cellular hypertrophy (Molkentin et al., 1998; Sussman et al., 1998). However, the physiologic relevance of this novel signaling pathway is presently uncertain and the subject of debate. Accordingly, the goals of the proposed study are: 1) To utilize transgenic mice expressing a peptide inhibitor of calcineurin in the heart to evaluate the role of calcineurin in mediating intrinsic forms of heart disease. 2) To utilize dominant negative calcineurin transgenic mice to determine the role of calcineurin signaling in pathophysiologic (extrinsic) forms of cardiac hypertrophy. Transgenic and pathophysiologic animal models are proposed to test the hypothesis that calcineurin/NF-AT act as a parallel regulatory pathway for cardiac reactive responses in vivo.
