Title of project: Cardiovascular disease: reducing the risk by vascular enzyme inhibition
Director of Studies: Dr John Skamarauskas
Second Supervisor: Dr Christopher Weston
Advisor Dr Sareen Galbraith
Overview of project
Cardiovascular diseases are the leading cause of death; a third of all deaths in 2005 were due to
heart disease. Annual European cardiovascular disease costs are £73 billion. Atherosclerosis is the
main contributory factor in cardiovascular disease development. Early intervention to reduce the
development of atherosclerosis will greatly alleviate the burden that cardiovascular disease poses to
society. Semicarbazide-sensitive amine oxidase (SSAO) is expressed by vascular cells and increased
activity is implicated in the pathogenesis of atherosclerosis, type I and II diabetes, smoking,
inflammatory diseases, obesity and cerebrovascular disease and strokes. The relationship between
SSAO activity and disease processes is poorly understood; direct damage to cells via oxidative stress
and aldehyde toxicity has been proposed as a key mechanism. Oxidation of low density lipoprotein
(LDL, "bad cholesterol") by SSAO is an important early step in the development of atherosclerosis
that has not been studied.
Link to Faculty Research Themes
School of Rehabilitation and Health Sciences and University of Birmingham. REF Units 5a (Biological
Sciences) or 2a: (Public Health, Health Services & Primary Care).
Outline of project including proposed timescales
Human SSAO will be expressed in eukaryotic cells. Purification of protein from these cells will allow
characterisation of SSAO at a molecular level. The student will determine enzyme kinetic parameters;
substrate inhibitors (semicarbazide, methylhydrazine) and effectors will be explored. Potential
substrates known to be associated with increased risk of cardiovascular disease, such as
aminoacetone, methylamine and allylamine, will be tested to understand their role in LDL oxidation. In
vivo activity of SSAO will be assessed by culturing cells in the presence of LDL and plasma lipids and
substrates. The ability of inhibitors to prevent or reduce oxidation of lipids will be evaluated.
The results from these studies will determine factors associated with an increased risk of
cardiovascular disease. A development pathway for a new class of drugs aimed at reducing the risk of
cardiovascular disease; together with high throughput screening of drugs will identify inhibitors of
SSAO with clinical and commercial potential. This project is a novel approach to develop
cardiovascular disease treatments, providing a rationale for prevention in known high risk groups,
which will be published in Circulation Research or Biochemical Pharmacology. A 3 year project grant
will be submitted to the British Heart Foundation to further develop this work examining the role of
SSAO in cardiovascular disease.
Further information
To apply you must be eligible for NHS Continuing Professional Development (CPD) funding and have
the support of your line manager in writing. General enquiries should be directed by email to the
Faculty Research Director r.hogston@leedsbeckett.ac.uk to discuss the project further please contact
the Director of Studies J.T.Skamarauskas@leedsbeckett.ac.uk
Applications should be made on line here
http://www.leedsbeckett.ac.uk/research/research-degrees/research-studentships-andfees-only-bursaries/