In the brain and spinal cord, nerves are covered by an insulating sheath of membrane called a myelin sheath. This allows fast transmission of electrical impulses and protects and maintains the nerve. In multiple sclerosis (MS), patches of demyelination occur, where these myelin sheaths are damaged and stripped off the nerve. This causes neurological symptoms such as paralysis, sensory changes and blindness. Replacement of these myelin sheaths (remyelination) can happen in MS, which can restore nerve function. This is generally inefficient, and often a scar forms instead, causing a long-term problem for the patient. Remyelination is carried out by oligodendrocyte precursor cells which are attracted to the damaged area, make contact with nerves, mature and form myelin sheaths to replace those that are damaged. A failure of remyelination can occur with a problem at any one of these steps. If we can understand the mechanisms of each step, we may be able to manipulate them to improve the efficiency of remyelination.
We want to:
- Understand why remyelination fails in Multiple Sclerosis, and
- Improve the efficiency of remyelination in MS.
To study this we use in vitro and ex vivo cultures of rodents and use human ES derived cells, human post mortem tissue and in vivo rodent and zebrafish models. We seek to understand better the remyelination process (often using imaging), and find targets to be able to manipulate it, using both candidate and screening approaches. We manipulate levels of molecules of interest with recombinant proteins, lentiviral transduction and using transgenic animals. We are particularly interested in molecules that control recruitment of oligodendrocyte precursor cells into demyelinated lesions, and are currently investigating small molecule inhibitors of chemorepulsive factors for OPCs.
Our group recently published on the therapeutic potential of drugs to reverse endothelial dysfunction in the treatment of Small Vessel Disease, a major cause of dementia and stroke. To obtain free access to this publication, follow the links below.
Rajani et al (2018). Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Science Translational Medicine 04 Jul 2018: Vol. 10, Issue 448, eaam9507. DOI: 10.1126/scitranslmed.aam9507 Abstract | Reprint | Full text
This video describes the work (Ranjani et al, 2018) and its implications.
- Clinical work: I am also an honorary consultant neurologist, and I carry out general neurology and MS clinics in the Royal Infirmary of Edinburgh.
New and noted
- MRC UK Regenerative Medicine Platform - Exploring the Stem Cell Niche Hub - Co-applicant, with Hub receiving £5.6 million. Starts Nov 2013 for 5 years.
- Scottish Senior Fellowship – May 2013-2017 £330k CSO - Targeting OPC migration towards remyelination therapies in multiple sclerosis May 2013. 12 months. £95k.
- Wellcome Trust Intermediate Fellowship - Semaphorins in the control of remyelination in multiple sclerosis– May 2008-May2013 - £824,795.
- Co-applicant for CSO grant with Prof. Steve Anderton - Probing regulatory T cells in multiple sclerosis brain Jan 2011-July 2012 - £165k.
- Wellcome Trust Institutional Strategic Support Fund (WT-ISSF)- Highly multiplexed single-cell RNA sequencing with Dr Keisuke Kaji and Dr Sally Lowell – June-sept 2012 - £20k
- Wellcome Trust Institutional Strategic Support Fund (WT-ISSF) - Label-free imaging of compact myelin;enabling high-throughput screens for novel remyelination therapies – with Prof. Alistair Elfick, Dr Rabah Mouras, School of Engineering, and Prof. Charles ffrench-Constant July -Nov 2012 - £50k
- Alzheimer’s Research UK Pilot Grant, Three-dimensional modelling of endothelial cell dysfunction in cerebral small vessel disease. 2016-2017 £50k
- GSK - CNS slice cultures as a tool for remyelination research – starts April 2015 for 2 years. £350k
- Sanofi-Genzyme - Identification of selective and potent inhibitors of the Semaphorin 3A Receptor Neuropilin-1 interaction on oligodendrocyte precursor cells to promote remyelination in Multiple Sclerosis – march 2015 for 2 years.
- MS society innovative grant - Optogenetic cell ablation in a focal CNS demyelination model in slice cultures – starts January 2015 for 1 year. £40k
- Prof Steve Anderton, University of Edinburgh
- Prof Chris Linington, University of Glasgow
- Prof Su Metcalfe, University of Cambridge
- Dr Pascale Durbec, University of Marseille
- Dr Lindy Fitzgerald, University of Western Australia
- Prof Robin Franklin, University of Cambridge
- Prof Charles ffrench-Constant, University of Edinburgh
- Dr Veronique Miron, University of Edinburgh
- Dr Alison Hulme, University of Edinburgh
- Dr Scott Webster, University of Edinburgh
- Dr Tara Spires-Jones, University of Edinburgh
- Prof Joanna Wardlaw, University of Edinburgh
- Prof Colin Smith, University of Edinburgh