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MRC DiMeN Doctoral Training Partnership: Systems-level understanding of calcium dynamics in cardiac cells, and functional effects of their modification in heart failure


Project Description

The mechanical function of the heart is driven by electrical activity through the process of excitation-contraction coupling. Intracellular calcium (Ca2+) signalling is a critical component of this coupling. Failure of normal Ca2+ homeostasis underlies inhibited contraction and vulnerability to arrhythmia associated with numerous cardiac conditions, including heart failure. However, our mechanistic understanding of how intracellular Ca2+ cycling processes regulate cell and tissue functions such as electrophysiology and contractility remains incomplete.

The failure of the recent CUPID-2 clinical trial, which targeted the SERCA2a Ca2+ pump to treat heart failure, highlights our incomplete understanding: despite downregulation of SERCA2a being hypothesised as a major contributor to abnormal Ca2+ cycling and cardiac dysfunction, gene therapy to upregulate SERCA2a failed to restore normal function. Nevertheless, interventions that correct abnormal Ca2+ cycling remain a key therapeutic target for several cardiac disorders including heart failure, and so a major focus now is on improving understanding of the integrated system to identify potent targets for intervention and adaptation of the abnormal system.

There is a clear need to understand in greater detail how Ca2+ cycling is controlled in cardiac cells, systematically identify the proteins or combination of proteins (the “control points” of the system) that play dominant roles in Ca2+ cycling, and mechanistically understand how modifications to these proteins (for example in heart failure) integrate to alter cell and tissue-level cardiac function. Computational models provide powerful research tools for undertaking such systematic evaluations. We have recently developed a novel, biophysically-detailed computational model of Ca2+ cycling in healthy cardiac cells, which we will apply to this problem.

The objectives of this project are: (i) Modify our validated model of healthy Ca2+ cycling to represent failing human cardiac cells, including accurate descriptions of remodelled Ca2+ fluxes, buffers, microdomains, protein phosphorylation and regulatory pathways; (ii) Use these models to identify control points of the Ca2+ handling system, quantify how modification of these control points affects subcellular, cellular and tissue-level cardiac physiology in health, and how this is modified in heart failure. The developed model will allow therapeutic interventions to be better targeted, potentially leading to novel treatments for heart failure and avoiding wasted clinical trials that modify isolated proteins with no functional effects.

Our research group: The Leeds Computational Physiology Laboratory uses a “systems biology” approach to study cardiac (patho)physiology, linking in vivo animal experiments, traditional ex vivo and in vitro electrophysiological approaches from the protein to the organ level, optical and MR imaging, and in silico computational modelling. Our computational models of human electrophysiology often provide an important link between animal experiments and clinical relevance. Developing, validating and characterising models describing how intracellular calcium is handled in human myocytes will enable us to plan our animal experiments, and interpret the results from these experiments, in a more focussed manner, particularly in situations where remodelled calcium handling is thought to be a trigger for arrhythmias, such as in heart failure. Please see http://www.physicsoftheheart.com for more details.


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.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Whittaker DG, Benson AP, Teh I, Schneider JE & Colman MA (2019) Analysis of the role of microstructure in ventricular arrhythmogenesis using image-based models. Biophysical Journal, in press (available online).

Colman MA, Pinali C, Trafford AW, Zhang H & Kitmitto A (2017) A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions. PLOS Computational Biology 13, e1005714.

Colman MA, Perez Alday EA, Holden AV & Benson AP (2017) Trigger versus substrate: multi-dimensional modulation of QT-prolongation associated arrhythmic dynamics by a hERG channel activator. Frontiers in Physiology 8, 757.

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