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Project 1: Small Molecular Modulators of Cardiac Hypertrophy and Failure: Target Identification and Translation to Drug Discovery
Overview
Diverse forms of cardiac stress, including myocardial infarction, hypertension, and contractile abnormalities trigger a cardiac remodeling process in which the heart becomes abnormally enlarged with consequent decline in cardiac function and eventual heart failure. During stress-induced hypertrophy, post-natal cardiac muscle cells increase in size and activate a set of fetal genes encoding proteins involved in stress-responsiveness, contractility, calcium handling, and myocardial energetics. We have shown that calcineurin, a calcium/calmodulin-dependent protein phosphatase, and several calcium-dependent protein kinases, couple diverse stress signals to pathologic cardiac growth and remodeling. These effectors initiate signaling cascades that culminate in the nucleus with the activation of the MEF2 transcription factor, a regulator of muscle-specific and stress-responsive genes. The transcriptional activity of MEF2 is governed by class II histone deacetylases (HDACs), which act as signal-responsive regulators of cardiac growth and gene expression. In the absence of stress signaling, class II HDACs interact with MEF2 (and possibly other transcription factors) and repress the fetal gene program and cardiac growth. Activation of HDAC kinases by hypertrophic agonists or biomechanical stress induces the phosphorylation of two conserved sites in class II HDACs, resulting in their dissociation from MEF2 and export from the nucleus, with consequent activation of MEF2 target genes and pathologic cardiac growth. The identification of nodal points in stress response pathways enabled us to design and execute high throughput screens for small molecules able to modulate hypertrophic signaling. As this project moves into the future, these small molecules will serve as essential tools to probe the pathophysiological significance of the signaling pathways we have discovered. Further, these molecules are potential candidates to emerge as novel therapies in patients with Atherosclerotic Heart Disease (ASHD). The long-term goals of this project are 1) to further refine our understanding of these cardiac stress-response pathways, 2) to validate the importance of specific regulatory proteins in the pathogenesis of heart disease, and 3) to develop novel small molecule inhibitors capable of preventing or reversing pathologic changes in the heart that lead to heart failure and sudden death. |
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Eric
N. Olson, Ph.D.
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