School of Medicine & Biomedical Sciences & Sheffield Teaching Hospitals NHS Foundation Trust
Does macrophage priming by hypoxia enhance arteriogenesis?
£17,695 - £20,484 per annum
Supervisor: Dr Tim Chico & Dr Steve Renshaw
Atherosclerosis reduces distal blood flow and induces hypoxia/ischaemia. This is improved by remodelling of pre-existing communications with other arterial territories to form "collateral vessels", a process termed arteriogenesis. Arteriogenesis reduce symptoms and improves survival, but no therapy is available that promotes arteriogenesis. The monocyte/macrophage is a key driver of arteriogenesis. Preventing macrophage recruitment to the site of vessel remodelling reduces, while promoting recruitment enhances arteriogenesis, though it is difficult to visualise macrophage / vascular interactions in vivo using conventional animal models. It is not known whether downstream hypoxia/ischaemia promotes arteriogenesis. Culturing macrophages in hypoxia directly induces several pro-arteriogenic genes. Equally, signals from hypoxic tissue may indirectly induce separate pro-arteriogenic pathways in macrophages that subsequently home to sites of vessel remodelling. We have developed zebrafish models of arteriogenesis and a transgenic zebrafish (fms:mCherry) that expresses the fluophore mCherry in tissue resident macrophages. These transparent embryos allow in vivo visualisation of cell movement and vessel remodelling. By Gal4:UAS transactivation we can specifically overexpress genes in macrophages and observe effects on migration and vascular remodelling.
Hypothesis; Hypoxia induces a pro-arteriogenic phenotype in macrophages and/or macrophage migratory behaviour that enhances arteriogenesis.
Aims and Objectives
1) Assess the effect of hypoxia on macrophage localisation at sites of vascular remodelling in zebrafish
2) Determine the transcriptomal response to hypoxia in tissue-resident zebrafish macrophages.
3) Overexpress candidate genes identified in objective 2 in normoxic zebrafish macrophages and assess effect on arteriogenesis
Training
The student will enter the generic research training program, comprising compulsory and self-selected components. They will obtain training in ethics, IT and essential laboratory documentation. Specific training will be received in zebrafish microinjection, light and confocal microscopy, FACS, microarray study design and analysis (via the BRU biostatistician), and molecular biology lab techniques (RNA extraction, real-time PCR, etc).
How to apply:
Please complete a University Postgraduate Research Application form and provide at least two references. To download the application form please visit: www.shef.ac.uk/postgraduate/research/apply/pgrform.html
Please clearly state ‘Medicine' and the prospective supervisors in the respective boxes.
Closing date: Monday 4th August 2008
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