Role of homoarginine in cardiac health and disease
Over the past 7 years, low plasma homoarginine (HA) has emerged as a novel independent risk factor for multiple cardiovascular diseases, e.g. stroke, myocardial infarction and heart failure. These association studies clearly indicate that serum HA is a biomarker for cardiovascular function and mortality. However, HA has no known metabolic or biochemical function and until recently was considered an exogenous metabolite of no significance.
Recent studies have raised the intriguing possibility that HA could have a direct effect on the disease process, such that artificially increasing HA levels might be considered beneficial. Our collaborators provided the first evidence for this, showing that treatment with exogenous homoarginine protects mice from ischaemic stroke. Similarly, we have data linking low homoarginine to impaired cardiac function and have shown that homoarginine supplementation improves contraction and relaxation in a murine model of heart failure.
This project will contribute to our understanding of the mechanisms involved by exploring the links between HA and putative effects on nitric oxide bioavailability, protein s-nitrosylation, and alkaline phosphatase. Homoarginine is now known to be biosynthesised by arginine:glycine amidinotransferase, which is also the first enzyme in creatine biosynthesis and may provide a link to whole body energy metabolism. The project will further seek proof-of-principle evidence for the therapeutic utility of homoarginine supplementation in other types of heart disease using preclinical models. It is easy to manipulate plasma levels in vivo since homoarginine is cheap, non-toxic and highly soluble; hence a positive outcome in the proposed project would have clear translational potential.
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), non-biased proteomic and metabolomic approaches, cell culture studies (e.g. confocal microscopy, 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.
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