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MBPhD Programme

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Best, Lawrence

Entered:

Sept 2015

Current Position (2019/20):

Post PhD: MBBS Year 5 - Life Cycle

PhD title:

The role of oligodendrocytes in recovery from stroke

Principal Supervisor:

Professor William, Richardson, Division of Medicine

Funding Source:

The Rosetrees Charitable Trust

Description of Project:

There are three main facets to my project. In the first strand I aim to build on recent progress on understanding the mechanism of motor learning in animal models, to investigate how this might be relevant to stroke and stroke recovery. My co-supervisor Professor William Richardson and colleagues recently showed that motor learning in healthy mice is dependent on the generation of new oligodendrocytes in the brain. This was demonstrated by conditional knock-out of a transcription factor, myelin regulatory factor (MyRF), in oligodendrocye precursor cells, thereby blocking the ability of those cells to generate new myelin-forming oligodendrocytes. I will use this model, superimposing stroke by middle cerebral artery occlusion and investigating whether their recovery is impaired or delayed relative to wild type mice. If so, this would indicate that newly-forming oligodendrocytes make a significant contribution to recovery. We will measure motor learning endpoints using behavioural tests. This primarily uses the “complex wheel” which is a running wheel with irregularly spaced rungs for which the mice require motor learning to adapt. In addition we will investigate the cellular processes using histochemistry for oligodendrocytes and myelin as well as other components of the acute cellular response such as astrocytes and microglia. Finally we will use MRI with my co-supervisor Professor Mark Lythgoe to quantify both functionally and structurally the extent of damage and recovery.

The second strand of my project involves development of MRI cell guidance methods. I hope to build on work previously done by Professor Mark Lythgoe in which he has demonstrated the ability to use magnetic resonance to target cells to particular areas of the body. We will attempt to apply this to the brain. If cells can be systemically injected into mice and targeted the brain this would constitute a breakthrough. This would mean that if a beneficial cell type can be discovered it could be injected acutely to try and prevent damage at the site of the stroke. Such a refined technique would hypothetically have few drawbacks in terms of unwanted effects.

The final aspect of my proposed project will have a clinical genomic approach. It will involve investigation of single nucleotide polymorphisms (SNPs) in genes such as the Myrf, Olig1 and Olig2 genes that are known to be required for timely myelination. In particular I will investigate whether SNPs in these gene are associated with differing patterns of motor recovery. To do this I will use a large case collection that is underway at UCL, also funded by Rosetrees Trust, supervised by my co-supervisor Dr Reecha Sofat.

 

Publications:

‘Microwave Ablation of Pulmonary Metastases Associated with Perioperative Takotsubo Cardiomyopathy’, Best, L., Seddon, B., Woldman, S., Lyon, A., and Illing, R. J Vasc Interv Radiol. 2014 Jul;25(7):1139-41

‘Reply to: ‘Re: “Microwave ablation of pulmonary metastases associated with perioperative Takotsubo cardiomyopathy”’’ Best L, Lyon A, Illing R. J Vasc Interv Radiol. 2014 Nov;25(11):1839-40

A previous version of this report was accepted by Interventional Oncology Sans Frontieres 2013 conference as a PowerPoint given to the attendees March 2013

‘Transcranial Doppler detection of microemboli as a predictor of cerebral events in patients with symptomatic and asymptomatic carotid disease: a systematic review and meta-analysis’ Best L, Webb A, Gurusamy K, Richards T. Presented orally at the European Society for Vascular Surgery Annual Meeting in Stockholm September 2014 and the completed article is currently being submitted for publication in the European Journal of Vascular Surgery

‘Surgical versus non-surgical treatment for oesophageal cancer (Protocol).’ Best LMJ, Gurusamy KS. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD011498. DOI: 10.1002/14651858.CD011498.

Teaching:

Awards & Prizes: