Grant: Operating Grant

Dilation related cardiomyopathies are cardiac diseases that manifest as an enlargement of cardiac chambers and are the most common cause of heart failure in North America. For over a decade, SCN5A gene has been associated exclusively to cardiac electrical abnormalities such as Brugada, the Long QT syndromes. Recently we identified a new SCN5A mutation where a hsitidien replaces the arginine on the S4 of the first domain (position 219) in a family with complex cardiac arrhythmias associated with DCM. We showed that that this resulted on leaky channels known as omega current. The association of the omega current with dilation characterized in this proposal is a novel hypothesis. We developed an in vivo model where the R219H human mutation was introduced in a mouse gene using gene targeting technique. The in vivo analysis of the homozygous and heterozygous mice showed that heart mice exhibit a dilation resembling what was described in human patient. The first objective is to characterize this mouse model and study the progression of the disease. The second objective of the proposal is to establish a cellular model of omega current using mouse embryonic stem cells differentiated into cardiac myocytes. This cellular model is of importance to ascertain that DCM is not the result of cardiac arrhythmias, know to generate dilated cardiac chamber as a compensatory mechanism. In conjunction with the mammalian expression model system, structural models containing DCM mutations will be undertaken as our third objective. The recent progress in crystallizing the homologous bacterial voltage-gated sodium channel, there is now sufficient understanding of the structure and function to anticipate useful data extrapolation for Nav1.5 function. As a forth objective we will express the isolated voltage sensors using a mammalian expression system this will provide a better signal-to-noise ratio.