About the Project
Motor neurones innervating postural muscles are relatively resistant to motor neurone disease (MND) but the mechanism is unknown. Neuromuscular junction (NMJ) degeneration is a very early pathological hallmark of the disease. We discovered two factors released at NMJs by activity that make NMJ transmission stronger for longer. Injecting one of these systemically (TGF-β2) can reverse motor signs for several weeks in MND mice. The other has not been tested and others may yet be discovered. We hypothesise such factors either confer disease resistance or are potential drug-targets to strengthen NMJs. This project will probe for further factors in transcriptomic differences between resistant and vulnerable motor neurone populations in health and disease, using an established mouse model and a new rat model of MND. Differential analysis will identify molecules/pathways relevant to nerve-muscle signalling as potential therapeutic targets. Finally, the best three candidate targets will be explored pharmacologically: both acutely ex vivo in isolated nerve-muscle preparations and chronically in vivo. We will evaluate their therapeutic efficacy on NMJ transmission, nerve-evoked muscle contraction and differential disease progression. The project is based in Aberdeen (30 months) and Edinburgh (6 months), and will utilise microarrays, transcriptomics, pathway analysis, NMJ histology, electrophysiology, neuropharmacology, and motor behaviour.
Prerequisites:
Background: Neuroscience, neuromuscular physiology, ideally with a knowledge/interest in MND.
Essential skills: Some wet-lab experience, preferably electrophysiology and/or molecular biology.
Desirable skills: One or more of the following - sharp electrode recording synaptic recording, mRNA extraction, PCR, microarray analysis.
Please contact your intended supervisor to discuss the project and your suitability for it before submitting your application.
The project is a part of SPRINT-MND/MS, a new Scotland-wide PhD scheme for research into motor neurone disease and multiple sclerosis. Projects, encompassing a wide range of topics including laboratory, clinical, and social sciences, are available at Aberdeen, Dundee, Edinburgh, Glasgow and St Andrews universities. This exciting initiative provides a great opportunity for budding researchers in any field related to MND or MS to join Scotland’s network of world-leading scientists and health professionals. Find more information here: http://www.edneurophd.ed.ac.uk/sprint-mndms-phd-programme.
Funding Notes
Studentships are for three years and include a standard non-clinical stipend*, UK/EU fees* and an allowance for consumables and travel. The cohort of SPRINT students will also be offered opportunities to attend clinics and meet patients, undertake ‘taster’ placements in a different field, and participate in public engagement and researcher networking events.
*Clinical and/or non-UK/EU applicants are eligible to apply. However, because any shortfall in stipend or fees must be met by the supervisory team, written agreement from the supervisor must accompany the application.
References
1. Fong SW, et al. .. & Bewick GS (2010). PNAS107:13515-9.
2. Fogarty JM, et al. .. & Bewick GS (2014). Proc Phys Soc 31:C17.
3. Day WA, et al. (2005). Neurobiol Dis. 19:323-30.
4. Miyasaka et al. (2016). Nature Methods (Submitted).
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