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The energetic requirements of the heart are weight-for-weight higher than for any other organ. This is met by continuously recycling a relatively small pool of adenosine triphosphate (ATP), which drives almost all energy consuming processes in the cell. Maintaining adequate levels of ATP is therefore critically important and multiple mechanisms have evolved to ensure that supply meets demand.

For example, the creatine kinase (CK) system acts as a spatial and temporal energy buffer with mitochondrial-CK (mito-CK) catalysing the transfer of a high-energy phosphoryl group from ATP onto creatine to form phosphocreatine (PCr) and ADP. PCr is then available for rapid regeneration of ATP catalysed by cytosolic CK dimers consisting of Muscle- (M-CK) and Brain- (B-CK) isoforms. ATP may also be generated via the activity of adenylate kinase (AK) which catalyses the reversible reaction 2ADP ↔ ATP + AMP.

Recent experiments overexpressing key components of these phosphotransfer systems in mice show protection from acute ischaemia and chronic heart failure, suggesting this may be a useful new therapeutic strategy for these deadly conditions. Our laboratory has recently generated novel transgenic models of CK and AK system augmentation and are now working to identify small drug-like molecules that have a similar effect. This project will expand our findings into other clinically-relevant models of cardiac disease and will seek to contribute to our limited understanding of how creatine, CK and AK are regulated in normal physiology and disease. It is hoped that these insights will provide potential therapeutic targets for manipulation in vivo.

Training Opportunities

Our laboratory, based in the Welcome Trust Centre for Human Genetics, is funded by a programme grant awarded by the British Heart Foundation.  The project would therefore take place within the context of a dedicated team of scientists, who have all the relevant experience, expertise and resources to provide full training in the required techniques. These will be wide-ranging from standard biochemical and molecular biology techniques (e.g. Western blot and PCR), cell culture studies (e.g. confocal microscopy, hypoxia/reoxygenation studies/siRNA knockdown) and in vivo quantification of cardiac function (e.g. echocardiography and invasive haemodynamics). Guidance will be provided via regular one-to-one meetings and lab meetings with the supervisors to evaluate progress and to set research goals. You will be encouraged to attend local scientific seminars and to develop your communication and networking skills by attending and presenting your own data at national and international meetings.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1 Neubauer S. 2007. The failing heart--an engine out of fuel.N. Engl. J. Med.,  356 (11), pp. 1140-51. http://www.ncbi.nlm.nih.gov/pubmed/17360992
2 Gupta A, Akki A, Wang Y, Leppo MK, Chacko VP, Foster DB, Caceres V, Shi S, Kirk JA, Su J, Lai S, Paolocci N, Steenbergen C, Gerstenblith G, Weiss RG. 2012. Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved.J. Clin. Invest.,  122 (1), pp. 291-302.  http://www.ncbi.nlm.nih.gov/pubmed/22201686
3 Lygate CA, Bohl S, ten Hove M, Faller KM, Ostrowski PJ, Zervou S, Medway DJ, Aksentijevic D, Sebag-Montefiore L, Wallis J, Clarke K, Watkins H, Schneider JE, Neubauer S. 2012. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction.Cardiovasc. Res.,  96 (3), pp. 466-75.  http://www.ncbi.nlm.nih.gov/pubmed/22915766
4

Zervou S, Whittington HJ, Ostrowski PJ, Cao F, Tyler J, Lake HA, Neubauer S, Lygate CA. Increasing creatine kinase activity protects against hypoxia / reoxygenation injury but not against anthracycline toxicity in vitro. PLOS ONE 2017;12:e0182994.  https://www.ncbi.nlm.nih.gov/pubmed/28806770

5 Zervou S, Whittington HJ, Russell AJ, Lygate CA. 2016. Augmentation of Creatine in the Heart.Mini Rev Med Chem,  16 (1), pp. 19-28. http://www.ncbi.nlm.nih.gov/pubmed/26202199
6 Zervou S, Yin X, Nabeebaccus AA, O'Brien BA, Cross RL, McAndrew DJ, Atkinson RA, Eykyn TR, Mayr M, Neubauer S, Lygate CA. 2016. Proteomic and metabolomic changes driven by elevating myocardial creatine suggest novel metabolic feedback mechanisms.Amino Acids,  48 (8), pp. 1969-81. http://www.ncbi.nlm.nih.gov/pubmed/27143170

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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