Dyadic cleft alteration in catecholaminergic polymorphic ventricular tachycardia

About the Project

The dyadic cleft is the biological structure responsible for the contraction of the cardiac myocyte and it is made of a calcium storage unit, the junctional sarcoplasmic reticulum (jSR) and a trigger unit the transverse tubule (t-tubule). In healthy individuals the juxtaposition of these units is defined by a strict geometry that allows the low voltage gated calcium channels (LTCCs), on the t-tubules, to stimulate the release of a well-regulated amount of calcium by the ryanodine receptors (RyR2) on the jSR. When this geometry is altered problems ensue affecting calcium release. If the calcium released in the myoplasm is not synchronised with the cell’s demands or is too abundant it causes arrhythmias.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by the onset of life-threatening arrhythmias during exercise or emotional stress. CPVT is caused by mutations of the ryanodine receptors (RyR2) or calsequestrin (CSQ2 and accessory protein of RyR2). These mutations predispose to calcium leak from the jSR that can lead to arrhythmias. Recent studies have shown that in CPVT caused by CSQ2 mutations there are significant alterations of the structure of the jSR with significant increase in jSR volume and surface area. To date no information is available on the structure of the jSR in CPVT caused by RyR2 mutations

We hypothesise that: The jSR and the geometry of the dyadic cleft is altered in all forms of CPVT.

A mouse model of RyR2 mutation (R2474S), closely reproducing the one found in human, and age matched controls will be used to test the hypothesis via the following aims and objectives:

• Altered dyadic cleft distance in CPVT. In control animals this distance has been verified to be ~15 nm. Electron microscopy will be used to obtain high resolution data in CPVT animals and compare them to controls.
• Altered jSR volume or surface area. Electron tomography will be used to compare jSR geometries in CPVT mice to those found in controls.
• Altered distribution/density of RyR2 on the jSR in CPVT. Electron tomography will be used, for the first time, to understand if the distribution of the RyR2 is different in CPVT compared to controls.

This project will establish if RyR2 mutations found in CPVT are linked to an altered geometry of the dyadic cleft or rather to a different distribution or density of the RyR2 on the jSR. Arrhythmia caused by CPVT will be linked to dyadic cleft remodelling or more precisely to RyR2 redistribution.

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Candidates with experience in electron microscopy or with an interest in image analysis are encouraged to apply.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cardiovascular Sciences Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website View Website