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Studying key components of the creatine kinase system to understand how they contribute to the pathophysiology of ischaemic heart disease and chronic heart failure.

Lygate

About the research

Studying key components of the creatine kinase system to understand how they contribute to the pathophysiology of ischaemic heart disease and chronic heart failure

We study how the heart meets its high and variable energy demands in order to identify novel strategies that may be 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 are exploring mechanisms to augment myocardial energetics as a therapeutic strategy to be tested in preclinical models of disease. We take a wide-ranging and holistic approach from molecules through cells to whole organs and organisms. As such, our projects would suit graduates with a background in biochemistry, pharmacology or physiology.

Student projects would align with one of two main areas of interest in our laboratory: -

Recent experiments overexpressing key components of the creatine kinase system in mice show protection from acute ischaemia and chronic heart failure, suggesting this may be a useful new therapeutic strategy for these deadly conditions. We are currently conducting an in vitro luciferase-reporter assay 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.

Our lab also has longstanding interest in creatine biosynthesis pathways. This is a two-step process that is initiated in the kidneys via the enzyme arginine:glycine amidinotransferase (AGAT). In the last few years it has become apparent that AGAT also produces the cationic amino acid, homoarginine (HArg), which, until recently, was considered an exogenous metabolite of no 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, fatal myocardial infarction and heart failure. We have shown in the AGAT knockout model that low HArg levels impair in vivo cardiac function and that supplementing the diet with HArg improves contractile reserve 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. The data gained would be used to support clinical studies of HArg supplementation as a potential adjunct therapy for chronic heart failure.

 

Training Opportunities

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.

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.

Publications

  
Cao F, Zervou S, Lygate CA “The creatine kinase system    as a therapeutic target for myocardial ischaemia-reperfusion injury” Biochem Soc Trans 2018 (in press). http://doi.org/10.1042/bst20170504     
Faller KME, Atzler D, McAndrew DJ, Zervou S, Whittington    HJ, Simon JN, Aksentijevic D, ten Hove M, Choe C, Isbrandt D, Casadei B,    Schneider JE, Neubauer S, Lygate CA. Impaired cardiac contractile function    in AGAT knockout mice devoid of creatine is rescued by homoarginine but not    creatine. Cardiovasc Res.    2018;114:417-430.  

 

Supervisors