The overall goal of the research proposed in this application is to develop novel therapeutic approaches, based on specific properties of an inherited molecular genetic defect, to the management of electrophysiological aberrations that occur in two forms (LQT-3 and LQT-1) of an inherited cardiac disorder, the long QT syndrome. This project is designed to integrate clinical, molecular, and cellular studies in order to test the overall hypothesis that mutations in genes that encode the heart sodium channel alpha-subunit (SCN5A), and the slow potassium channel current (IKs) KvLQT-1/or minK cause identifiable changes in expressed sodium and potassium channel activity that underlie diseased-associated changes in repolarization and associated rhythm disturbances and that, in turn, make mutant channels distinct targets of therapeutic drugs. Thus, it is the long-term goal of this research to develop a more effective and specific therapeutic approach to manage and prevent life-threatening arrhythmias associated with this disease and that therapies will be developed that are targeted for specific gene defects. In vitro experiments will be carried out using patch-clamp procedures to measure whole-cell currents expressed in human embryonic kidney cells (HEK293) and Chinese hamster ovary (CHO) cells that have been transiently transfected with cDNAs encoding wild-type (hH1) and LQT-3 mutant (deltaKPQ) forms of the human sodium channel alpha-subunit as well as cells that have been co-transfected with cDNA encoding wild-type and mutant forms of KvLQT1 and minK. Experiments focusing on possible roles of adrenergic modulation, cellular pH and calcium influx will test for voltage-dependent kinetic and neurohumoral factors that may distinguish KvLQT-1 from SCN5A-derived phenotypes. In addition, experiments will be carried out on each gene defect testing for specific pharmacological interventions that are designed to modulate expressed channel activity in a manner to compensate for individual gene defects. The principal investigator will consult with Dr. Arthur J. Moss at the University of Rochester, who will be directing parallel clinical studies in order to optimize pharmacological approaches to manage and correct identified gene defects. Experimental data obtained from recombinant channel activity will be shared and integrated with the results of clinical non-invasive electrocardiologic studies that will be carried out in vivo on carriers vs. non-carriers of the LQT-1 and LQT-3 gene mutations to optimize experimental design and therapeutic approaches.
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