Lowri Thomas Email & Phone Number

Cardiff, Gb

Swansea, United Kingdom

Investigating how different dysfunctional gating mechanisms at the single channel level result in arrhythmia. The resulting Ca2+-release/contraction will be assessed both in recombinant cell systems and in induced pluripotent stem cell derived cardiac myocytes (both patient derived and genome edited) as human cell models of arrhythmic disease (in collaboration with Prof Chris Denning, University of Nottingham). Both single molecule and cell systems will be used to assess whether these… Show more Investigating how different dysfunctional gating mechanisms at the single channel level result in arrhythmia. The resulting Ca2+-release/contraction will be assessed both in recombinant cell systems and in induced pluripotent stem cell derived cardiac myocytes (both patient derived and genome edited) as human cell models of arrhythmic disease (in collaboration with Prof Chris Denning, University of Nottingham). Both single molecule and cell systems will be used to assess whether these different mechanisms influence the efficacy of RyR2-targeted drugs. I am also interested in the functional effects of RyR2 channel clustering, a phenomenon being investigated using droplet-interface bilayer technology (in collaboration with Dr Oliver Castell, Cardiff University School of Pharmacy). Show less

Mutations in RyR2 are known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a disorder characterised by adrenergic induced arrhythmias leading to possible sudden cardiac death. These symptoms are attributed to inappropriate Ca2+ release from ‘leaky’ RyR2 channels though the precise molecular mechanism is in question and this is the main subject of my research. This began by defining how the wild type human channel gates – using Single Channel Analysis. Mathematical… Show more Mutations in RyR2 are known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a disorder characterised by adrenergic induced arrhythmias leading to possible sudden cardiac death. These symptoms are attributed to inappropriate Ca2+ release from ‘leaky’ RyR2 channels though the precise molecular mechanism is in question and this is the main subject of my research. This began by defining how the wild type human channel gates – using Single Channel Analysis. Mathematical modelling of this data resulted in mechanistic description which revealed novel aspects of channel gating, including the presence of rare, brief unliganded channel openings (Mukherjee et al, 2012). The modelling work carried out to date will serve as a template against which the effects of disease causing mutations and physiological modulators of RyR2 can be studied, as well as providing a base for assessing the influence of therapeutic compounds capable of stabilising RyR2 function in pathological conditions. I’m hoping to extend this work using an induced pluoripotent stem cell model of CPVT (in collaboration with Professor Chris Denning, University of Nottingham). Luminal Ca2+ regulation is thought to play a major role in determining the ‘leakiness’ of mutant RyR2 channels and mutations of the Ca2+ storage protein calsequestrin have also been linked to CPVT. As such, I am also interested in studying the regulation of mutant channels by luminal accessory proteins. Channel dysfunction in various channelopathies can be modulated by co-inherited polymorphisms and we are also investigating the effects of such phenomena on RyR2 function (in collaboration with Dr Chris George ). Show less

Doctor Of Philosophy (Ph.D.), Molecular Genetics

The cardiac Ryanodine Receptor (RyR2) controls Ca2+ release from the intracellular store during excitation-contraction coupling. Genetic.

Bachelor'S Degree, Genetics, 1St Class