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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Cincinnati Children's Hospital Medical Center
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Purcell, Nicole H; Darwis, Dina; Bueno, Orlando F et al. (2004) Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes. Mol Cell Biol 24:1081-95
Bueno, Orlando F; Lips, Daniel J; Kaiser, Robert A et al. (2004) Calcineurin Abeta gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction. Circ Res 94:91-9
Braz, Julian C; Bueno, Orlando F; Liang, Qiangrong et al. (2003) Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest 111:1475-86
Parsons, Stephanie A; Wilkins, Benjamin J; Bueno, Orlando F et al. (2003) Altered skeletal muscle phenotypes in calcineurin Aalpha and Abeta gene-targeted mice. Mol Cell Biol 23:4331-43
Bueno, Orlando F; Wilkins, Benjamin J; Tymitz, Kevin M et al. (2002) Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice. Proc Natl Acad Sci U S A 99:4586-91
Wilkins, Benjamin J; De Windt, Leon J; Bueno, Orlando F et al. (2002) Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol 22:7603-13
Bueno, Orlando F; Molkentin, Jeffery D (2002) Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 91:776-81