Molecular mechanisms of electrical remodeling in cardiac hypertrophy

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

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