RESEARCH INTERESTS
Calmodulin in cardiovascular diseases
Long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are inherited conditions that disturb heart rhythm and can cause life-threatening arrhythmias (e.g. sudden cardiac death). Recent studies have identified mutations in the major calcium sensor calmodulin (CaM) that are associated with cardiac arrhythmia susceptibility suggesting that CaM dysfunction is a key driver of the molecular aetiology of these diseases. However, the detailed molecular mechanism leading to irregular heartbeats in LQTS and CPVT remains unclear.
Schematic representation of calcium-induced calcium release (CICR) in cardiac muscle cell
Cartoon representation of the crystal structure of calcium-bound CaM (grey) in complex with RyR1 peptide (green) (PDB 2BCX) highlighting some LQTS and CPVT mutations (red). Calcium ions are presented as yellow spheres.
We aim to determine the role of CaM and the effect of the disease-causing mutations in the regulation of calcium fluxes during cardiac excitation-contraction coupling using a multidisciplinary approach including protein biophysics, electrophysiology, structural biology and cellular imaging. Through a comprehensive structure-function analysis characterising the effect of CaM mutations on its interaction network relevant to cardiac muscle contraction, we will develop a detailed mechanistic understanding of congenital heart dysfunctions which will open ways to future therapies.
Development of fluorescent protein probes for biological applications
Using site directed mutagenesis on genetically-encoded probes or chemical labelling with environmentally sensitive fluorophores, we aim to improve the biophysical properties of calcium, glutamate and glucose probes for in vivo imaging.
Calcium-binding proteins in neurodegenerative disease
We employ a multidisciplinary approach to understand the role of calcium-binding proteins in dystonia and pain relief. we are particularly interested in the regulation of calcium channels by small calcium-binding proteins.
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FUNDING SOURCE
We are currently funded by the British Heart Foundation and the Wellcome Trust.
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