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Defining the structural basis of arrhythmia: How do long QT syndrome-associated calmodulin mutations affect ion channel activity


Faculty of Health and Life Science

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Dr N Helassa , Prof C Dart No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

We are looking for a highly motivated student to work with us on an exciting 3-year British Heart Foundation (BHF)-funded project to define the molecular basis of cardiac arrhythmias.

To work effectively as a pump the heart muscle contracts in a perfectly timed rhythm which is controlled by electrical activity within the heart cells (the heartbeat). Disruption to this rhythm (arrhythmia) compromises the heart’s ability to deliver oxygenated blood to the body and can be life-threatening. Long QT syndrome (LQTS) is an inherited condition that disturbs heart rhythm and can cause life-threatening arrhythmias. It is a cardiac arrhythmia syndrome with an estimated incidence of 1/2000. It has a mortality rate of 21% for symptomatic patients who do not receive therapy within one year.

Recent human genetic studies have identified mutations in the major calcium sensor calmodulin (CaM) that are associated with LQTS susceptibility, suggesting that CaM dysfunction is a key driver of the molecular aetiology of this disease. However, the detailed molecular mechanism leading to irregular heartbeats in LQTS remains unclear. In this project, we will determine the effect of the disease-associated CaM mutations in the regulation of ion channels during cardiac muscle contraction using a multidisciplinary ‘molecule to function’ approach. We will use comprehensive structure-function analyses to characterise the effect of CaM mutations on ion channel activity and develop a detailed mechanistic understanding of congenital heart dysfunctions which will open ways to future therapies.

This is an exceptional opportunity for the successful applicant to receive comprehensive research training in techniques ranging from molecular cloning, protein biochemistry, structural biology and electrophysiology. The successful applicant will also gain experience in dissemination of scientific knowledge by preparing articles for publication and through presenting findings at both national and international research conferences. In the Institute of Life Course and Medical Sciences (ILCaMS), regular access to journal clubs and weekly meetings will provide valuable exposure to working within a multidisciplinary environment. Broader research training will also be provided through the University’s PGR training programme and doctoral training college.

The student will be supervised by Dr Nordine Helassa, BHF Research Fellow in Cardiovascular Science and Prof Caroline Dart who will provide training and support in all relevant techniques. The project will be hosted in the Department of Cardiovascular and Metabolic Medicine in ILCaMS. https://www.liverpool.ac.uk/life-course-and-medical-sciences/

We are looking for a highly motivated student who is willing to pursue cutting-edge research within a vibrant and collegiate team. A basic background in protein biochemistry would be beneficial. The ILCaMS is fully committed to promoting and supporting equality, diversity and inclusion. In recruitment, we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

Essential eligibility requirements:
• BSc (minimum 2.1 honours degree) in a related discipline.
• Excellent communication skills.

Enquiries to: Dr Nordine Helassa ([Email Address Removed]) or Prof Caroline Dart ([Email Address Removed])

To apply: Applicants should send a CV, covering letter (2-page max), and the names of at least two references to Dr Nordine Helassa, [Email Address Removed]

Expected interview date/week: 15th December 2020

Funding Notes

This is a fully-funded PhD studentship which covers:
• University fees for 3 years at UK or EU postgraduate student rates (NOT Overseas), £4,407 for 2020 – 21
• Generous student stipend for 3 years, £19,919 for 2020 – 21
• A total of £23,500 research costs to cover the whole 3-year period of the study

References

1: Chazin WJ, Johnson CN. Calmodulin Mutations Associated with Heart Arrhythmia:
A Status Report. Int J Mol Sci. 2020 Feb 19;21(4):1418. doi:
10.3390/ijms21041418. PMID: 32093079; PMCID: PMC7073091.

2: Jensen HH, Brohus M, Nyegaard M, Overgaard MT. Human Calmodulin Mutations.
Front Mol Neurosci. 2018 Nov 13;11:396. doi: 10.3389/fnmol.2018.00396. PMID:
30483049; PMCID: PMC6243062.
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