The applicant's long-range goals are to define the biological roles and regulation of K channels in heart and skeletal muscle.
The specific aims of this proposal are: (1) To develop a transgenic mouse model deficient in the expression of cardiac voltage-gated K channels using a dominant negative approach by over-expression of a truncated K channel (Kv1.1N206). It is anticipated that such a transgenic mouse may be an appropriate animal model for the long QT interval syndrome. Included in this aim are description of the biochemical, biophysical and pharmacological properties of the K channels expressed in the hearts of transgenic mice, and monitoring of the heart rhythm for possible ventricular arrhythmias in transgenic mice. (2) To determine the individual amino acids that play a role in the dominant negative effect of Kv1.1N206 in vitro and in vivo. This includes determining the amino acids responsible for in vitro folding and assembly of Kv1.1N206 into multimeric complexes, and determining the amino acids which are responsible for the dominant negative effect in Xenopus oocytes. (3) Elucidation of the mechanisms that regulate cell-specificity and the level of expression of the gene coding for the K channel, Kv1.5. This includes studies of the cis- regulatory sequences and transacting nuclear factors that modulate the cell-specific expression of Kv1.5, and characterization of a DNA element (KPE) that regulates the level of expression of Kv1.5 promoter in GH3 cells.
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