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Realising the therapeutic potential of creatine and homoarginine in heart disease


   Radcliffe Department of Medicine

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  Prof C Lygate  No more applications being accepted  Self-Funded PhD Students Only

About the Project

We study how the heart meets its high and variable energy demands in order to identify novel strategies that may be therapeutically beneficial in disease. Central to this is the creatine kinase system, which represents the primary short-term energy buffer that maintains myocardial ATP levels when demand outstrips supply. We are studying key components of this system to understand how they contribute to the pathophysiology of ischaemic heart disease and chronic heart failure, which are both major killers worldwide. In particular, we explore strategies to augment myocardial energetics and test whether these are beneficial in preclinical models of disease. 

Our experiments overexpressing key components of the creatine kinase system in mice show reduced injury and improved recovery from myocardial infarction, suggesting this may be a useful new therapeutic strategy for this deadly condition. We are currently conducting an in vitro drug screen in collaboration with Astra-Zeneca to identify small molecules that increase myocardial creatine levels. Future work will characterise these new compounds and test them in preclinical models of ischaemic heart disease, including proof-of-principle studies in angina and peripheral vascular disease. We will explore the molecular mechanisms and determine whether cardioprotection is additive to existing therapeutic strategies and whether it persists in common co-morbidities, such as diabetes.

Creatine is synthesised in a two-step process initiated in the kidneys by the enzyme arginine:glycine amidinotransferase (AGAT). In recent years it was discovered that AGAT also produces the cationic amino acid, homoarginine (hArg), which, until recently, was considered a minor metabolite of no known biochemical significance.  However, low plasma hArg has emerged as a novel independent risk factor in human populations, associated with increased mortality from stroke, sudden cardiac death, myocardial infarction and heart failure. We have shown that AGAT knockout mice with low hArg levels have impaired cardiac function that can be rescued by giving dietary hArg. Furthermore, we have shown that supplementing the diet with hArg improves contractility in a murine model of chronic heart failure. Ongoing work is aimed at establishing optimal dosing and pinning down the underlying molecular mechanisms via candidate and non-biased approaches, e.g. proteomics, metabolomics, and RNA-sequencing. We are exploring mechanisms of AGAT regulation and the potential interactions that might occur between creatine and hArg in the heart and other metabolically active tissues. It is hoped that these findings will ultimately lead to clinical trials of hArg supplementation as a potential adjunct therapy for chronic heart failure.

Our laboratory, based in the Welcome 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.

Additional supervision will be provided by Dr Sevasti Zervou.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

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.

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.

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 build a happy and rewarding environment where all staff and students are supported to achieve their full potential.


References

1 Lygate CA. The Pitfalls of in vivo Cardiac Physiology in Genetically Modified Mice - Lessons Learnt the Hard Way in the Creatine Kinase System. Front Physiol. 2021; 12:685064. doi: 10.3389/fphys.2021.685064.
2 Cao F, Maguire ML, McAndrew DJ, Lake HA, Neubauer S, Zervou S, Schneider JE, Lygate CA. Overexpression of mitochondrial creatine kinase preserves cardiac energetics without ameliorating murine chronic heart failure. Basic Res Cardiol. 2020; 115(2):12. doi: 10.1007/s00395-020-0777-3.
3 Cao F, Zervou S, Lygate CA. The creatine kinase system as a therapeutic target for myocardial ischaemia-reperfusion injury. Biochem Soc Trans. 19; 46(5):1119-1127. doi: 10.1042/BST20170504.
4 Whittington HJ, Ostrowski PJ, McAndrew DJ, Cao F, Shaw A, Eykyn TR, Lake HA, Tyler J, Schneider JE, Neubauer S, Zervou S, Lygate CA. Over-expression of mitochondrial creatine kinase in the murine heart improves functional recovery and protects against injury following ischaemia-reperfusion. Cardiovasc Res. 2018;114(6):858-869. doi: 10.1093/cvr/cvy054.
5 Faller KME, Atzler D, McAndrew DJ, Zervou S, Whittington HJ, Simon JN, Aksentijevic D, Ten Hove M, Choe CU, Isbrandt D, Casadei B, Schneider JE, Neubauer S, Lygate CA. Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine. Cardiovasc Res;114(3):417-430. doi:
10.1093/cvr/cvx242.
6 Atzler D, McAndrew DJ, Cordts K, Schneider JE, Zervou S, Schwedhelm E, Neubauer S, Lygate CA. Dietary Supplementation with Homoarginine Preserves Cardiac Function in a Murine Model of Post-Myocardial Infarction Heart Failure. Circulation. 2017;135(4):400-402. doi: 10.1161/CIRCULATIONAHA.116.025673.

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