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Discovering the neuronal signalling mechanism at the heart of human heart disease

   Faculty of Biological Sciences

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  Dr Izzy Jayasinghe, Prof E White, Prof N Gamper  No more applications being accepted  Competition Funded PhD Project (European/UK Students Only)

About the Project

Background: Cardiac dysrhythmia a leading cause of mortality and long-term morbidity worldwide. Over 25% of these originate in the heart’s electrically-autonomous (pacemaking) cells without a detectable heart attack. Inappropriate release of calcium from internal compartments (e.g. endoplasmic reticulum) into the cytoplasm of pacemaker cells is central to this pathology. Recent reports suggest that a small group of intracellular calcium channels, ryanodine receptor type-3 (RyR3) – historically associated with neuronal signalling underpinning learning and memory – can interact with other calcium handling proteins to trigger dysrhythmogenic calcium signals. The molecular mechanism and locations of RyR3 and its partners seeding these dysrhythmias are unknown.
Objectives: (i) To locate RyR3 and its partner proteins which trigger dysrhythmogenic 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-dysrhythmic therapies target other calcium handling proteins and involve significant risks. Identification of RyR3 and partners as a trigger mechanism for dysrhythmia 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 dysrhythmogenic calcium signals at an unprecedented spatial resolution.
Approach: With the primary supervisor, you will exploit the latest super-resolution microscopy tools (DNA-PAINT and Expansion Microscopy), to visually examine how RyR3s are organised in the pacemaking (sinoatrial node) cells of healthy hearts. You will study a rat model prone to dysrhythmias, and atrial biopsies obtained from human patients with a history of dysrhythmia. Harnessing the novel super-resolution microscopy techniques called EExM and sandSTORM pioneered in our group in Leeds, you will compare how RyR3, IP3-receptors and SERCA proteins are re-arranged in the nanometre-scale during the pathology. You will map the dysrhythmogenic calcium signals against the underpinning RyR3 and partner protein layouts using a novel correlative microscopy protocol developed by the primary supervisor for overlaying calcium and DNA-PAINT images. With pharmacological inhibitors of IP3R and SERCA established by another co-supervisor for studying dorsal root ganglion neurons, you will modulate the calcium handling of RyR3 and partners to understand how the signals can be reverted towards a healthy phenotype.
Key outcomes will include mechanistic schemes of the molecular-scale factors in RyR3-mediated calcium signals seeding dysrhythmia and a set of pharmacological strategies to impede them.

Funding Notes

The Faculty of Biological Sciences is pleased to announce a number of fully-funded PhD studentships to start in Oct 2019, covering academic fees at UK/EU level and providing a stipend at research council rate (£15,009 for 2019-20) for 4 years. Candidates should have, or be expecting, a 2.1 or above at undergraduate level in a relevant subject. A range of projects, spanning the research areas of the faculty, are eligible for funding. Please apply online, clearly stating which project/supervisor you are interested in and including a CV and transcripts.We do not require a research proposal.
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