Rassf1A signaling in cardiac hypertrophy, fibrosis and failure

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DESCRIPTION (provided by applicant): Despite recent progress in medical therapy, heart failure is one of the most common causes of death in western countries. Understanding the molecular mechanism mediating growth and death of cardiac muscle is fundamentally important and can potentially lead to better medical treatment for heart failure. This laboratory has been working on an enzyme termed mammalian sterile 20-like kinase 1 (Mst1) which plays an essential role in regulating growth and death of cardiac myocytes. Although this enzyme is activated in the heart in response to high blood pressure and during heart failure, the molecular mechanism by which Mst1 is activated in the heart is not well understood. The aims of this project are to investigate the role of putative regulators of Mst1, termed Ras-association domain family 1, isoform A (RassfIA) and K-Ras, in mediating the activation of Mst1, growth and death of cardiac myocytes, and the resulting impact on heart function. Genetically altered RassfIA and K-Ras mice will be subjected to transverse aortic constriction and used to study the role of RassfIA in the development of cardiac hypertrophy and heart failure. Echocardiography, hemodynamic analysis, post-mortem organ measurements, histology and biochemical analysis will all be used to determine and compare resulting cardiac phenotypes. The possibility that RassfIA can modulate cardiac fibrosis will also be addressed with a focus on NF-KB as a potential mediator. Cultured cardiac myocytes and fibroblasts will serve as tractable systems to allow for the examination of signaling pathways involving RassfIA and Mst1. This work will also seek to evaluate K-Ras as an upstream activator of this signaling pathway in the heart. The knowledge obtained from this investigation will further elucidate the mechanism of Mst1 regulation in vivo and should be useful for the development of better treatment for heart failure.