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Exploring the similarities between neointimal formation after vascular injury and tumour growth


   Bristol Medical School

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Rationale
Vascular smooth muscle cell (VSMC) proliferation leads to intimal thickening, which causes reoccurrence of symptoms (restenosis) in 30-50% of coronary artery disease patients receiving saphenous vein grafts and individual receiving stent implantation. Currently there are no effective treatments which reduce VSMC proliferation and intimal thickening in saphenous vein grafts or coronary stents. Consequently, there is a critical need therefore to identify new approaches that will reduce intimal thickening without detrimental effects on the endothelial coverage. The uncontrolled growth of VSMCs has marked similarities to that observed within numerous tumours and cancers. Indeed, we have recently discovered the potential for adventitial cells with characteristics of VSMCs to disseminate and contribute to the formation of neointimal formation ex vivo.

Aims and objectives
The aim of this current studentship is to use in vitro, ex vivo, and in vivo models to ascertain if adventitial myofibroblasts, perivascular VSMCs, or other adventitial cells with VSMC characteristics contribute to neointimal formation. Approaches to modulate such cells could then be assessed to indicate whether this such an approach could be beneficial for reducing intimal thickening and enhancing patency of vein grafts.

Methods
The techniques to be used are all routine in our group and include flow cytometry, tissue culture, molecular biology, microscopy and imaging, in vitro and in vivo cell behavioural assays, as well as numerous in vivo and ex vivo models of cardiovascular disease. Detailed bioinformatics will also be deployed to mine and analyse the differential expression patterns between the adventitial cells and validate key findings in human tissue samples. In the final year of the project, the plan will be to assess the effect of modulating the cells in models of vascular injury. As such, this project would suit a student with an interest in the understanding of human disease and therapeutics. It offers the opportunity to study in an excellent research environment, in a research institute with world class facilities and resources, devoted to understanding the cellular and molecular mechanisms of cardiovascular disease, and driving new translational therapies and identification of biomarkers for patients susceptible to cardiovascular diseases.

References

1.Farooq V, Gogas BD, Serruys PW. Restenosis: Delineating the Numerous Causes of Drug-Eluting Stent Restenosis. Circulation: Cardiovascular Interventions. 2011;4(2):195-205.

2.Parang P, Arora R. Coronary vein graft disease: Pathogenesis and prevention. Canadian Journal of Cardiology. 2009;25(2):E57-E62.

3.Lyon CA, Wadey KS, George SJ. Soluble N-cadherin: A novel inhibitor of VSMC proliferation and intimal thickening. Vascular Pharmacology. 2016;78:53-62.

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