This proposal describes a 5-year training program to develop an academic career in molecular cardiac electrophysiology. The principal investigator has extensive training in clinical cardiac electrophysiology, basic electrophysiology, biophysics, and electrical engineering and will expand his scientific skills through a unique integration of interdisciplinary resources. This program will promote the command of molecular developmental biology, as applied to the development of cardiac arrhythmias and conduction disorders. Dr. Michael Parmacek will mentor the principal investigator's scientific development. He is a recognized leader in the field of molecular cardiac development and has trained numerous postdoctoral fellows and graduate students. To enhance the training, an advisory committee of highly regarded medical scientists will provide scientific and career guidance. The research will focus on mechanisms of arrhythmogenesis produced by mutations in the metabolic sensor AMP-activated protein kinase. Recent work has shown that mutations in AMP kinase produce familial Wolff-Parkinson-White syndrome in humans, and mice engineered with inhibitory mutations in their hearts die suddenly. The proposed experiments will use a combination of in vivo and in vitro electrophysiologic studies, biochemical and molecular techniques, and in situ localization analysis. We will study mice engineered with constitutively activating and inhibitory mutations in AMP kinase to elucidate the arrhythmogenic mechanisms of AMP kinase in the whole heart to the molecular level.
The specific aims i nclude: 1) determining the effect of mutations in AMP kinase upon cardiac arrhythmia inducibility, 2) determining if mutations in AMP kinase alter ion channel function, 3) determining if ion channel distribution is affected by mutations in AMP kinase that contribute to arrhythmogenesis. This will be the first functional analysis of how AMP kinase produces electrophysiologic disorders and may provide insight into novel mechanisms of arrhythmogenesis. The Cardiovascular Division of the University of Pennsylvania provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized training programs. Such an environment maximizes the potential for the principal investigator to establish scientific expertise from which to launch an independent academic career.
