Academic Vascular Surgery Research Unit

Research purpose: The academic vascular surgery research unit (AVSRU) was established in 2003 to investigate the aetiology of degenerative vascular diseases.The overall aim of our research is to identify new therapeutic targets for stabilisation of atherosclerotic plaques and aortic aneurysms.Whilst development of atherosclerotic plaques and aortic aneurysms share a number of common processes eg., inflammation, thrombosis, angiogenesis, and apoptosis, they are strikingly different in that whilst atherosclerotic plaques can naturally stabilise, remaining clinically silent indefinitely, the ultimate fate of the aneurysm is to rupture.

Research Strategy: Observations from analysis of proteins, messanger RNAs and specific cells, of human tissues sampled from consenting patients have defined hypotheses which we are testing at the pre-clinical level.Hypotheses which are borne out in pre-clinical testing will be translated to clinical trials were practically possible.Currently we have two clinical strategies under investigations:

[1] The ability of reconstituted High-density lipoprotein (rHDL) particles to promote plaque stability in patients undergoing carotid endarterectomy — we are measuring the ability of a short infusion of rHDLs to alter the expression profile of the plaque from an unstable to a stable phenotype.

[2] The use of thiazolidenediones (TZD) to stabilise abdominal aortic aneurysms — patients with small aneurysm will be prescribed either TZD or placebo and the rate of growth of the aneurysm measured using ultrasound over a period of two years.

Research Facilities:.

(i) Exclusive facilities:

• Our tissue culture suite provides facilities to isolate primary lines and propagate cells.The isolation of cells from human-derived material is separate from material derived from pre-clinical models.Time-lapse and phase-contrast imaging is also available in our laboratory.

• We have the facilities necessary to perform histological and immuno-histochemical analysis of paraffin and cryo-preserved tissue sections, and excellent facilities for photomicrography and morphometric analysis of tissue sections.

• The protein laboratory has equipment necessary for western blot analysis (mainly signal transduction molecules), electrophoretic mobility shift assays of nuclear proteins, as well as ELISA and other immunologically based protein assays.

• We have laboratory facilities required to study gene expression using RNase protection assay and northern blotting.

• Video micrometry and micro-dissection facilities are specific to our laboratory.

(ii) Core facilities:

• Biological Research Facilities in which we have established pre-clinical models of vascular diseases necessary for proof-of-principle and safety studies prior to translational work.

• The Biomics Centre provides equipment and necessary software for quantitative real-time PCR analysis and DNA array analysis, as well as equipment for protein mass spectrometry.

(iii) Collaborative facilities:

• MRI imaging — in collaboration with Dr Franklyn Howe we have been able to establish the using of the 4.7 Tesla magnet to measure aneurysms in our pre-clinical models.

• Infra-red imaging (Li-Cor Biosciences) will be available, in the BRF, through collaboration with

• Flowcytometry — in collaboration with Dr Jenny Tooze (Department of Clinical Haematology) we are able to do single, dual and three-colour FACS and cell sorting.

Clinical Infrastructure of Aneurysm Research:

Professor Matt Thompson, Professor of Vascular Surgery at St George’s Hospital NHS Trust and Clinical Lead of AVSRU, has the largest aneurysm practice in the UK, and has 8 consultants.The Vascular Unit will be commencing a screening programme for males over 65 year in the future, and these patients, and age matched controls will be recruited into proposed research projects. The Clinical Trials Unit, administered through the Vascular Unit, provides a dedicated unit, with its own infrastructure for introducing translational research into clinical practice. The Trials Unit has over a decade of experience in running multi-centre clinical trials.

Research Funding:

Equipment:Most equipment, with the exception of the -80^oC freezers, and the invert-phase fluorescence microscope, was purchased through a ‘laboratory start-up’ grant awarded to Dr Cockerill by the Garfield Weston Foundation.The freezers and fluorescent microscope (which is a communal facility) was funded through the St George’s Charitable Foundation Equipment Users Committee.Blood pressure monitoring equipment was purchased thorough an award made by the FH Muirhead Charitable Trust.

Research salaries and consumables: Research consumables and staff salaries have been funded through awards from the British Heart Foundation, Wellcome Trust, British Cardiac Society, National Heart Foundation, Royal College of Surgeons as well as Industry (Medtronics, Pfizer, Merck Sharp and Dohme and Cooke).