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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL089319-03
Application #
7765574
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Carlson, Drew E
Project Start
2008-06-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$136,350
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Das, Saumya; Aiba, Takeshi; Rosenberg, Michael et al. (2012) Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation 126:2208-19
Rosenberg, Michael A; Das, Saumya; Pinzon, Pablo Quintero et al. (2012) A Novel Transgenic Mouse Model of Cardiac Hypertrophy and Atrial Fibrillation. J Atr Fibrillation 2:1-15
Shah, Ravi V; Altman, Robert K; Park, Mi Young et al. (2012) Usefulness of hemoglobin A(1c) to predict outcome after cardiac resynchronization therapy in patients with diabetes mellitus and heart failure. Am J Cardiol 110:683-8
Cook, Stuart A; Varela-Carver, Anabel; Mongillo, Marco et al. (2010) Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction. Eur Heart J 31:100-11
Harjes, Daniel I; Dubach, J Matthew; Rosenzweig, Anthony et al. (2010) Ion-selective optodes measure extracellular potassium flux in excitable cells. Macromol Rapid Commun 31:217-21
Singh, Sheldon M; Barrett, Conor D; Das, Saumya (2010) Pseudo-atrial fibrillation due to non-reentrant AV nodal tachycardia. Europace 12:36
Dubach, J Matthew; Das, Saumya; Rosenzweig, Anthony et al. (2009) Visualizing sodium dynamics in isolated cardiomyocytes using fluorescent nanosensors. Proc Natl Acad Sci U S A 106:16145-50
Das, Saumya; Makino, Seiko; Melman, Yonathan F et al. (2009) Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation. Heart Rhythm 6:1146-53
Singh, Sheldon M; Das, Saumya (2008) Delayed heart block after temporary balloon occlusion of a secundum atrial septal defect. Circ Arrhythm Electrophysiol 1:405-6