We propose renewal of the Specialized Center of Research in Sudden Death at the University of Utah. Our long-term objective continues to be an investigation of the relationship between abnormal repolarization and ` arrhythmic death. The goal of this investigation is development of therapies that prevent sudden death through fundamental observations at the bench. To achieve this goal we propose six inter-related research projects supported by four core laboratories. Twenty-two investigators are involved. Molecular Genetics of Ventricular Arrhythmias is led by MT Keating. He will identify new mutations underlying the hereditary long QT syndrome (LQT) and idiopathic ventricular fibrillation (IVF), both of which are caused by ion channel dysfunction during repolarization. MC Sanguinetti and MF Sheet, in Molecular Physiology of LQT and IVF, propose biophysical studies of the mutant and wild type disease genes discovered by Keating. Cellular electrophysiological mechanisms of Repolarization, is headed by KW Spitzer. This explores electrophysiological mechanisms of repolarization-related arryhthmias, including contributions by intercellular coupling defects, intracellular calcium and the sodium/calcium exchanger. Project 4, Measurement of Repolarization led by RL Lux, provides new methods for precise measurement of cardiac repolarization and in homogeneities of recovery in humans which are essential if we are to link the basic science observations in the previous Projects with the human trials of Projects. Project 5, Prognostic Value of Repolarization Measures, headed by LS Green, continues a clinical study initiated in the previous grant cycle with the goal of discovery measures of repolarization that predict subsequent sudden death after acute myocardial infarction. Repolarization-related prognosticators in other conditions are also human treatment component of this SCOR. Gene- based pharmacologic therapies of LQT and IVF are proposed. Administration, Instrumentation, Cell Processing and Signal Processing Core laboratories support the six projects. The structure of this multi-disciplinary research effort has been optimized to develop knowledge from disease gene discoveries and rapidly translate it to prevention of sudden death.
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