Grant: Project Grant

Heart rhythm disturbances known as cardiac arrhythmias are a major medical concern as they can cause sudden death. For over a decade, SCN5A gene has been associated exclusively to cardiac electrical abnormalities. Recently we identified a new mutation on SCN5A gene where a histidine replaces the arginine (position 219) in a family with complex cardiac arrhythmias associated with dilated cardiomyopathy. We showed that that this resulted on leaky channels named gating pore currents. We developed an in vivo model where the R219H human mutation was introduced in a mouse gene using gene targeting technique. The first objective is to characterize and compare two mouse models and study the progression of the disease. The second objective of the proposal is to establish a cellular model of the gating pore current using human induced pluripotent stem cells known as hiPSCs differentiated into cardiac myocytes. We will evaluate the phenotypic reversal in hiPSC-CMs from DCM patient using a new genome editing technology called CRISPR/Cas9. The overall objective of the research project is to develop an animal model and a human cellular models to study the mechanisms accountable for irregular heartbeats and explore ways to reverse cardiac phenotypes using genome editing.