The role of brain endothelial cells in multiple sclerosis
Dr A Williams
Prof A Baker
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
The newly established four-year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme will combine medical science and translational research projects with integrated and credited teaching in science communication, public engagement, patient involvement, data design and informatics, via established MSc courses and/or new Engagement for Impact courses. Our vision is to teach a generation of researchers equipped to address and solve real-world problems through excellent science and who have the engagement and impact skills we believe will give them an edge in their future careers.
This potential PhD project, selectable by successful applicants to this Programme, is supervised by Prof. Anna Williams (http://www.crm.ed.ac.uk/research/group/remyelination-multiple-sclerosis) at the Centre for Regenerative Medicine, with co-supervisor Prof. Andrew Baker.
Brain endothelial cells (ECs) are implicated in a variety of brain diseases, including cerebral small vessel disease (cSVD), through their signalling to the underlying brain including oligodendrocytes. ECs in disease can become ‘dysfunctional’ detectable by increased EC proliferation (amongst other markers). In this state, they secrete substances (including HSP90a) which inhibit the maturation of oligodendrocyte precursors (OPCs) into mature myelinating oligodendrocytes. Reversal of EC dysfunction in vitro reduced HSP90a release and improved OPC maturation, and in vivo normalised cSVD white matter.
Multiple sclerosis (MS) also shows pathology suggestive of the blood vessel and EC involvement with more blood vessels in the vicinity of MS demyelinated lesions2 and angiogenesis3. We also now know that ECs in a mouse CNS model of demyelination (EAE) are dysfunctional using transcriptomics4. This leads to the hypothesis that dysfunctional ECs also contribute to the pathology of MS, adversely affecting the ability of OPCs to mature into myelinating oligodendrocytes, hence limiting one of the routes to remyelination and brain repair.
This project will address this hypothesis using 1) bioinformatic analysis of EC heterogeneity and dysfunction from current RNAseq datasets, 2) spatial validation on MS and mouse model tissue and 3) drug reversal of EC dysfunction, e.g. with simvastatin, in a treatment trial in a demyelinating mouse model, aiming to improve remyelination.
1. Rajani et al., 2018 PMID: 29973407, 2. Holley et al., 2010 PMID: 20036712, 3. Seabrook et al., 2010 PMID: 21176212, 4. Munji et al., 2019 PMID: 31611708
Engagement for Impact:
This project is centred on the neurodegenerative disease multiple sclerosis (MS). The student will be part of the MS Society UK-funded MS Centre and so will have much opportunity for public engagement through the centre and through the charity itself. AW is a MS Society Ambassador and a clinician, carrying out NHS clinics in the Anne Rowling Regenerative Neurology Clinic at Little France, with therefore access to around 3000 people with MS. This clinic is also involved in the current simvastatin trial in MS, MSSTAT2 (ClinicalTrials.gov Identifier: NCT03387670). The project is based in the CRM/IRR, which runs the science mentorship scheme at Castlebrae High School http://www.crm.ed.ac.uk/community-science-engagement and is involved with teacher training as stem cell biology is part of the new science curriculum.
This is one of the potential projects in the University of Edinburgh College of Medicine and Veterinary Medicine’s new 4 year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme. Successful applicants will select their preferred PhD projects from the available options in discussion with proposed supervisors. Three studentships are available in the programme, providing full tuition fees (EU/UK rate only), stipend of at least £15,000 per year, £450 annual travel and conference allowance, dedicated engagement support grant of £1,500, and £5,000 annually towards research consumable costs.
Apply before 26th January 2020 at https://www.ed.ac.uk/inflammation-research/postgraduate-training/phd-programme