PhD opportunity with the MRC DiMeN Doctoral Training Partnership
Discovering the neuronal signalling mechanism at the heart of cardiac arrhythmias
Objectives: (i) To locate RyR3 and its partner proteins which trigger arrhythmogenic calcium signals in pacemaker cells at nanometre precision (ii) To use pharmacological inhibitors tested previously on neuronal cells for perturbing the calcium signals inappropriately triggered by RyR3.
Timeliness: A number of current anti-arrhythmic therapies target other calcium handling proteins and involve significant risks. Identification of RyR3 and partners as a trigger mechanism for arrhythmias in pacemaker cells would be crucial to developing alternative and potentially safer therapies.
Novelty: RyR3, until now, has not been linked with heart disease. This project will utilise the latest super-resolution microscopy tools like Expansion Microscopy and DNA-PAINT to pinpoint the epicentres of arrhythmogenic calcium signals at an unprecedented spatial resolution.
Key outcomes will include mechanistic schemes of the molecular-scale factors in RyR3-mediated calcium signals seeding arrhythmias and a set of pharmacological strategies to impede them.
Research environment: You will be embedded in the Nanoscale Microscopy Group, nested within the Cardiovascular Research group in the University of Leeds (working with Dr Izzy Jayasinghe and Prof Ed White). This is one of the UK’s leading clusters of researchers examining the cellular mechanisms of cardiovascular diseases. You will form bridges between this group, Prof Nikita Gamper of the Leeds Neuroscience group, Badrilla Ltd which is one of the leading specialists of analytical reagents for the cardiovascular sciences, and our international collaborators in Australia, New Zealand and USA.
Benefits of being in the DiMeN DTP: This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research. We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
2. Ouyang, K. et al. Ca2+ sparks and secretion in dorsal root ganglion neurons. PNAS. 2005; 102 (34) 12259-12264
3. Jayasinghe, I. et al. Shining new light on the structural determinants of cardiac couplon function. Frontiers in Physiology. doi: 10.3389/fphys.2018.01472