Many strategies have emerged to improve the function of the blood vessel wall following acute injury, including targeting endothelial cell function, vascular smooth muscle cell proliferation and migration and adventitial progenitor cells. microRNA are small non-coding RNA that have the capacity to target many hundreds of genes through targeting seed sequences in the 3’UTR. We have shown the miRNA are essential in vascular smooth muscle cell function and development of vascular remodelling (Deng 2015/MacDonald2013). We have identified novel miRNA that have the capacity to block vascular smooth muscle cell proliferation. A major step forward would be the development of novel approaches to deliver therapeutic miRNA into the vessel wall by virus-based delivery approaches. Working with the Dr Havenga over many years has facilitated the development of novel aderiovirus-based vectors for gene therapy (Waddington Cell, 2008).
Recently, we have identified, purified and tested a novel human adenovirus vector that displays effective delivery of genes to endothelial cells but very restricted delivery to th liver - the main site of adenovirus vector accumulation. Further, this virus shows very low levels of pre-existing neutralisation in the general population (approximately 10% vs 60% for human adenovirus 5) making this a very attractive virus for application to human gene therapy. In this project we will, therefore, test this vector (and other novel promising vectors that become available during the course of the project) in the setting of vascular gene therapy post injury of the vasculature. The project will therefore have outstanding training potential in:
• Virology, vector construction and propagation • In vitro cell culture of vascular cells • In vivo models of acute vascular injury and delivery of virus • Evaluation of therapeutic miRNA in vivo.
The project additionally benefits from a collaboration on the development of therapeutic miRNA with the Giacca lab in Trieste, Italy.
Applications: Completed application form along with your curriculum vitae should be sent to our PGR student team at [email protected]
References: Please send the reference request form to two referees. Completed forms for University of Edinburgh College of Medicine and Veterinary Medicine project should be returned to [email protected] by the closing date: 1st April 2019.
All candidates should have or expect to have a minimum of an appropriate upper 2nd class degree. To qualify for full funding students must be UK or EU citizens who have been resident in the UK for 3 years prior to commencement.