Epidemiologic studies implicate family history as a distinct risk factor for sudden cardiac death, and multiple lines of evidence implicate SCN5A, encoding the cardiac sodium channel -subunit, as a candidate gene. These include in vitro experiments, molecular genetic studies, and large clinical trials (CAST) that converge on decreased sodium channel availability as a common cause for arrhythmias. The goal of this Project is to delineate new mechanisms determining this reduced channel availability. Preliminary studies have identified enhanced slow inactivation of the channel with oxidative or drug stress, cloned and undertaken initial characterization of the 5'-flanking region driving expression of SCN5A, and identified non-coding and coding region polymorphisms. The latter do not alter channel availability at baseline but do under oxidative or other stress conditions.
Specific Aims 1 will identify structural domains in the channel underlying enhanced slow inactivation with oxidative stress, and Specific Aim 2 will delineate enhancer and repressor elements controlling SCN5A transcription;
both aims will include studies of the functional effects of DNA polymorphisms.
Specific Aim 3 will directly test the hypothesis that DNA variants are arrhythmogenic at baseline or with stress by studying the electrophysiologic properties of mice generated by recombination-mediated cassette exchange to carry a series of variant sodium channels. The identification of DNA variants that enhance arrhythmic risk will be an important step in stratification of risk for sudden death, while delineation of domains of the channel crucial for arrhythmogenic behavior will identify new targets for drug intervention. By advancing our understanding of this aspect of the biology of arrhythmia susceptibility, these studies mesh well with the overall theme of this Program.
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