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Using zebrafish models to investigate cerebral arteriovenous malformations


Project Description

Cerebral Arteriovenous Malformations (cAVM) relate to a spectrum of conditions associated with blood vessel abnormalities of the brain [1]. cAVM present as a ‘tangle’ of abnormal connections between arteries and veins in the brain, which frequently lead to bleeding within the brain. cAVM are almost always congenital and are thought to arise from an error in blood vessel formation in early pregnancy. Although rare, affecting 1 in 1,000 people, and seemingly harmless in about a third of patients, cAVM can have devastating life-changing and life-threatening consequences such as seizures, brain haemorrhage or stroke. cAVM are a young person’s disease; the average age of those seeking medical attention being only 34 years. Treatment options for patients are largely focused on neurosurgical intervention. We still do not fully understand the pathophysiology of cAVM and as such no specific medications are currently available.

We are studying the molecular mechanisms associated with the formation of abnormal arterio-venous connections in cAVM. In cAVM, the ‘angioarchitecture’ (i.e. the shape and size of these blood vessel abnormalities) can change, and in some cases new blood vessels develop in a process called angiogenesis. Experimental work has shown that a signalling protein called Vascular Endothelial Growth Factor (VEGF), which stimulates angiogenesis, is found at high levels in cAVM and represents a promising treatment target [2], however further investigation is necessary. Using zebrafish disease models [3-5], we aim to further characterise the development of cAVMs over time and investigate the role of defective angiogenic processing in this pathology. Furthermore, we will perform pharmacological intervention studies to determine whether manipulation of angiogenesis signalling pathways (e.g. VEGF inhibition) can limit cAVM formation. This work will improve our understanding of the role of VEGF in cAVM development and determine whether VEGF represents a realistic therapeutic target for this condition in the future.

Training/techniques to be provided:
Home Office personal licence.
Zebrafish disease modelling.
Phenotyping.
Live imaging.
Molecular biology.
Immunohistochemistry.
Drug screening.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in zebrafish disease modelling and/or with an interest in cerebrovascular disease are encouraged to apply.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

1. Solomon, R.A. and E.S. Connolly, Jr., Arteriovenous Malformations of the Brain. N Engl J Med, 2017. 376(19): p. 1859-1866.
2. Mouchtouris, N., et al., Biology of cerebral arteriovenous malformations with a focus on inflammation. J Cereb Blood Flow Metab, 2015. 35(2): p. 167-75.
3. Rochon, E.R., P.G. Menon, and B.L. Roman, Alk1 controls arterial endothelial cell migration in lumenized vessels. Development, 2016. 143(14): p. 2593-602.
4. Roman, B.L., et al., Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development, 2002. 129(12): p. 3009-19.
5. Sugden, W.W., et al., Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic clues. Nature Cell Biology, 2017. 19(6): p. 653-665.

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