The long-long objectives of our research project are to understand the molecular basis for heterogeneity in K channel function in normal heart, and the mechanisms for alterations in K channel function in diseased heart. In normal heart, the pattern of K channel heterogeneity helps maintain the cardiac electrical stability. Perturbations of such normal heterogeneity will likely predispose the heart to arrhythmias. Such situation occurs in hypertrophied/failing hearts where alterations in K channel function contribute to a dispersion of repolarization, setting the stage for reentrant arrhythmias. To design effective therapies for these pathological conditions, it is important to know, at the molecular level, what causes such a normal pattern of K channel distribution and how it is perturbed in diseased heart. The focus of this proposal is the transient outward (Ito), slow delayed rectifier (IKs) and rapid delayed rectifier (IKr) currents, the three major repolarizing K currents in cardiac myocytes. We will use dog as our animal model, and compare K channel function in normal hearts and in hearts with chronic myocardial infarction where various remodeling processes have occurred. We will apply the techniques of electrophysiology, molecular biology, immunoblotting and immunocytochemistry to examine channel function and subunit expression. The strategy is to use an iterative process between experiments on native channels in cardiac myocytes and experiments on channel clones expressed in in vitro systems to establish a correlation between subunit composition and channel function.
Four Specific Aims are proposed. Under the first 3 Aims, we will study why the current density and gating kinetics of Ito, IKs and IKr, respectively, are heterogeneous in normal heart. The information, as well as the tools (K channel subunit cDNAs and antibodies) we develop during these Aims, will be applied under Aim 4 to examine the molecular basis for K channel remodeling in postinfarction heart. Results from these experiments will provide new insights into molecular physiology and pathology of cardiac K channels, which will aid the design of therapeutic interventions for arrhythmias in postinfarction remodeled hearts.
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