Role of Modulation of Ito,f by Kinases in Cardiac Dysrhythmias

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DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in molecular cardiac electropathophysiology. The principal investigator is a pathologist with an expertise in cardiac electrophysiology and cardiopulmonary pathology, and through this program he will expand upon his scientific and investigative skills. The Cardiovascular Research Institute of the University of Rochester Medical Center will provide the principal investigator with an ideal setting for studying the molecular mechanisms involved in cardiac dysrhythmias under the expert guidance of experienced mentor Dr. Jun-lchi Abe and committee members Drs. Bradford Berk and Mark Taubman, and with additional support from consultants Drs. Jose Jalife and Robert Dirksen. The proposal focuses on the role of the p90 Ribosomal S6 Kinase (p90RSK) in cardiac dysrhythmias, which are a leading cause of morbidity and mortality in different types of heart disease. Based on the preliminary data, the experimental hypothesis is that activation of pQORSK reduces lto,f channel activity via phosphorylation of Kv4.3, prolongs cardiac repolarization, and predisposes to dysrhythmias in cardiac disease. To investigate the role of modulation of It0.f by p90RSK in cardiac dysrhythmias three specific aims are proposed: 1) Determine the molecular mechanism by which lto,f is modulated by p90RSK. 2) Determine the molecular mechanism by which activation of p90RSK prolongs action potential duration and predisposes to dysrhythmias via inhibition of lto,f channel activity. 3) Determine if perturbing p90RSK signaling reduces frequency of dysrhythmias induced by cardiac ischemia/reperfusion and myocardial infarction via preventing downregulation of lto,f channel activity. Irregular heart rhythms are a common cause of morbidity and mortality in patients with heart disease This research will investigate the effects of the protein p90 Ribosomal S6 Kinase on heart rhythms. The results of these studies will enhance our knowledge of the molecular basis of these abnormalities and could lead to development of new therapies for their treatment and/or prevention. (End of Abstract)