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(MRC DTP) Understanding the mechanisms responsible for aberrant atrial calcium handling in heart failure


Project Description

Atrial fibrillation (AF) is the most common cardiac arrhythmia, expected to affect ~18 million Europeans by 2060. AF often occurs in patients with heart failure (HF), increasing their risk of death by ~2 fold. When AF and HF occur together treatment options are extremely limited and so preventing AF occurring in HF could prevent the large increase in mortality.
In the normal heart a rise in intracellular calcium causes contraction and occurs when calcium is released from the calcium store, the sarcoplasmic reticulum, via clusters of RyR calcium release channels. This calcium release occurs at discrete release sites throughout the cell although little is known about the structure and function of these sites in the atria. We (and others) have shown that HF-related aberrant remodelling of calcium handling in the atria not only reduces the rise in intracellular calcium (1,2) and contraction, but also predisposes to the development of AF (3). Our recent unpublished data, using state of the art super-resolution microscopy (STORM imaging) and confocal calcium imaging, reveals that in HF atrial cells the function of calcium release sites is decreased. Remodelling of subcellular structures, notably disorder of RyR clusters, likely plays a key role in this dysfunction and may contribute to the onset of AF in HF. What causes this remodelling of atrial RyRs is unknown but at least in the ventricle RyR phosphorylation is thought to play a role.
This cutting-edge interdisciplinary project will use tissue and cells from a translationally relevant animal model of HF and recovery from HF. Super-resolution (STORM) imaging will be coupled with advanced three-dimensional electron microscopy and computational modelling to provide novel insight into the mechanisms underlying this clinically relevant problem.
The main aims will be to:
1) determine structural and functional factors responsible for the remodelling of atrial RyR clusters in HF
2) establish for the first time if atrial stretch, brought about by ventricular dysfunction in HF, underlies atrial RyR cluster remodelling
3) determine if RyR cluster remodelling is reversible and if this has therapeutic potential
4) use data obtained in the project to direct advanced computer models to predict how remodelling contributes to abnormal atrial electrophysiology and alters the propensity for AF in HF.

https://www.research.manchester.ac.uk/portal/katharine.dibb.html
https://www.research.manchester.ac.uk/portal/andrew.w.trafford.html
http://www.jordiheijman.net/
https://www.research.manchester.ac.uk/portal/christian.pinali.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1) Dibb KM, Clarke JD, Horn MA, Richards MA, Graham HK, Eisner DA and Trafford AW. Characterization of an extensive transverse tubular network in sheep atrial myocytes and its depletion in heart failure. Circ Heart Fail. 2009;2:482-9
2) Clarke JD, Caldwell JL, Horn MA, Bode EF, Richards MA, Hall MC, Graham HK, Briston SJ, Greensmith DJ, Eisner DA, Dibb KM and Trafford AW. Perturbed atrial calcium handling in an ovine model of heart failure: potential roles for reductions in the L-type calcium current. J Mol Cell Cardiol. 2015;79:169-79.
3) Molina CE, Abu-Taha IH, Wang Q, Roselló-Díez E, Kamler M, Nattel S, Ravens U, Wehrens XHT, Hove-Madsen L, Heijman J, Dobrev D (2018). Profibrotic, Electrical, and Calcium-Handling Remodeling of the Atria in Heart Failure Patients With and Without Atrial Fibrillation. Front Physiol. 9:1383. doi: 10.3389

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