Molecular mechanisms of electrical remodeling in cardiac hypertrophy

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DESCRIPTION (provided by applicant): This grant will support a 5-year period of rigorous training for the development of a career as an independent investigator in academic cardiac electrophysiology. The principal investigator has completed his clinical fellowship in cardiology and electrophysiology at Massachusetts General Hospital and seeks to expand his scientific skills using a unique integration of resources. This proposal seeks to investigate the mechanisms of electrical remodeling that accompany cardiac hypertrophy. The candidate will be under the joint mentorship of Dr. Anthony Rosenzweig, the Director of Cardiovascular Research at Beth Israel Deaconess Medical Center, who has expertise in the field of cardiac hypertrophy and kinase signaling pathways, and Dr. Patrick Ellinor, Assistant Professor of Medicine at MGH, who has expertise in the field of cardiac ion channel structure-function. A curriculum encompassing both research and didactic training will be devised to further the training of the candidate, and an advisory committee of leading medical researchers will provide scientific and career advice. Sudden cardiac death and ventricular arrhythmias (VA) are a leading source of mortality in patients with congestive heart failure. Myocardial hypertrophy precedes heart failure and is an independent predictor of VAs. However, the signaling cascades that link hypertrophy to the electrical remodeling that comprises the substrate and is the source of triggers of lethal VAs are not well understood as yet. We have recently shown that the PI-3 kinase-dependent serum glucocorticoid-responsive kinase (SGK-1) can modulate cardiac hypertrophy in response to diverse stimuli. SGK-1 uniquely targets several ion channels, and our new and exciting preliminary data suggest that SGK-1 can phosphorylate and alter the trafficking of the voltage-gated cardiac sodium channel SCNSa in cardiomyocytes. The overall goal of the proposal is to test the hypothesis that SGK-1 is an important mediator of the electrical remodeling in cardiac hypertrophy by addressing the following specific aims. We propose 1) To determine if SGK-1 is necessary and sufficient for hypertrophy-induced changes in SCNSa. 2) To examine the role of SGK-1 in regulation of SCNSa function, and 3) To evaluate if SGK-1 is a mediator of electrical remodeling associated with cardiac hypertrophy. These aims will be achieved using a combination of biochemical, molecular biological and electrophysiological techniques in vitro as well as by in vivo studies in mice subject to genetic manipulation. Completion of these aims will provide a deeper understanding of the molecular basis of cardiac electrical remodeling. Insights into the critical mechanistic links between hypertrophy and electrical remodeling may lead to newer therapeutic options in an area of great clinical importance. Furthermore the proposal will serve as an ideal platform for the candidate to make the transition to an independent investigator.