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The effect of age on arterial remodelling: relevance to atherosclerotic plaque progression and aneurysm formation


   Bristol Medical School

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  Prof S George, Dr J Johnson  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Brief Rationale
Atherosclerosis is an inflammatory vascular disease involving plaques composed of lipid-dense cores filled with activated, apoptotic and necrotic inflammatory and vascular cells coated with a fibrous cap. The rupture of these plaques is associated with prevalent ischemic diseases such as myocardial infarction and stroke (1). Therefore, inhibition of the progression of these plaques towards an unstable and rupture-prone phenotype is of particular therapeutic interest. Similarly, the prevention of aneurysm formation and progression is also of clinical relevance and importance. Aneurysms are characterised by cellular and molecular remodelling within the vessel wall leading to weakening and risk of eventual rupture and haemorrhage (2). Both atherosclerosis and aneurysms are known to involve arterial remodelling. Age is a well-documented risk factor for both atherosclerotic plaque and aneurysm formation. We have recently observed that arterial remodelling is exaggerated in carotid arteries from old mice after to ligation compared to young mice. However, the mechanism for this is unknown. We have observed differences in markers of Wnt signalling in old and young cells and tissue and aim to determine whether this contributes to the exaggerated signalling.

We hypothesize that arterial remodelling is exaggerated with age due to altered Wnt signalling and this is a contributing factor to atherosclerotic plaque rupture and aneurysm formation.

Aims and Objectives
This project aims to understand the molecular basis of the altered remodelling. This project will investigate the underlying mechanisms using genomic and proteomic approaches in both human samples and mouse models.

For this PhD, the student will undertake in vitro experiments on samples obtained from the following patients. Samples will be used from the Bristol Coronary Biobank, Bristol Aneurysm Biobank and collected from surgery. The student will gain valuable experience in a number of techniques including cell culture, flow cytometry, immunocytochemistry, Q-PCR, Western blotting and histology. In vivo experiments will also be performed to validate findings in a mouse model.

References

1. Hansson, G.K., and Libby, P. (2006). The immune response in atherosclerosis: a double-edged sword. Nature reviews immunology 6(7):508-519.

2. López-Candales, A., Holmes, D.R., Liao, S., Scott, M.J., Wickline, S.A., Thompson, R.W., (1997) Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. The American Journal of Pathology, 150(3):993-1007.