Probing local CaMKII activation in ventricular myocytes and the role of CaMKII in arrhythmogenesis.

Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. A large fraction of these arrhythmiasare thought to be initiated and perpetuated through a loss of a normal intracellular Ca2+ homeostasis, causing abnormal electrical activity andproarrhythmogenic events, which possibly involves calcium-calmodulin dependent kinase II (CaMKII). In physiological conditions, CaMKII regulates numerous intracellular proteins (RyR, LTCC, phospholamban) in the excitation-contraction coupling of myocytes. A dysregulation of the CaMKII activation and its subsequent downstream effects could be at the base of developing arrhythmogenic events. However, until now the underlying CaMKII-dependent mechanisms in arrhythmias are still poorly understood. Therefore, in this project we will investigate both up- and downstream pathways of CaMKII activity. Combining electrophysiology, confocal Ca2+ imaging and molecular techniques in single myocytes, we will study local activation of CaMKII by dyadic Ca2+ release, and how this differentially regulates subpopulations of downstream targets. These 
findings will then be corroborated in a large animal model with enhanced susceptibility to arrhythmias, to understand the role of local CaMKII activity in Ca2+-dependent electrical instability causing arrhythmogenic events.

Keywords:Calcium-calmodulin dependent kinase, Myocyte, Dyadic cleft, Alectrophysiology, Arrhythmia

Disciplines:Cardiac and vascular medicine

Project type:PhD project