Wellcome Trust Clinical PhD Programme at the University of Oxford: Redox regulation of protein phosphorylayion in the fibrillating atrial myocardium. (360G-Wellcome-099898_Z_12_Z)

Atrial fibrillation (AF) is the most common, sustained, cardiac arrhythmia and is a significant cause of stroke and heart failure. The pathogenesis of the condition is poorly understood, but it is known to be associated with remodelling of the electrophysiological properties and structure of the atrial myocardium. Evidence indicates that at least some of the changes in ion currents and transporter activity result from differences in PKA-mediated phosphorylation. Recent findings show that an altered nitroso-redox balance can directly activate PKA activity and redistribute phosphorylation to different subcellular targets, independent of cyclic GMP. The aim of the project is to explore the role of nitrosative and oxidative stress in the regulation and sub- cellular localisation of protein phosphorylation in AF through the use of real-time imaging by fluorescence resonance energy transfer (FRET) techniques in human and murine atrial myocytes. Specific aims 1. Generation of protein-targeted FRET biosensors for the detection of cAMP and PKA activity in myocardial sub-cellular domains in health and disease. 2. Investigation of mechanisms underlying the changes in second messengers and kinase activity in atrial fibrillation (AF) : myocardial effect of disrupting nitric oxide signalling and increasing oxidase activity.