About the Project
Spinal Muscular Atrophy (SMA) is a devastating motor neurone disease of very young children and is the leading inherited cause of infant death. Although the genetic defect, protein affected (SMN) and disease pathology are all well characterised, we do not understand the mechanism by which SMN1 depletion results in SMA pathology. Parson group has evidenced the importance of the circulatory system in the aetiology of SMA: aberrant development of blood vessels in skeletal muscle and spinal cord are associated with tissue hypoxia in mouse models and SMA patients (1); developmental defects in liver (2) and spleen (3) are linked by abnormal/ delayed growth of blood vessels (angiogenesis), governed by changes in vascular endothelial factor (VEGF) and its receptors (VEGFR). Gillingwater group have developed a line of research implicating defective ubiquitination as a downstream, drug-targettable factor in SMA pathology (reviewed in 4), but its mechanism of action remains unclear. Recently a direct link between ubiquitination and angiogensis has been made (5), which allows us to propose a sequence of molecular events downstream of SMN depletion.
This project aims to determine the sequence of events and identify drug-targets toward developing more effective combinatorial therapies, in conjunction with antisense treatment (Spinraza), for SMA.
Prerequisites:
A broad education in morphology at gross and microscopic levels. Experience of some molecular techniques would be an advantage. Interest and enthusiasm to solve problems and make observations is essential.
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.edinburghneuroscience.ed.ac.uk/edneurophd/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. Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy. Somers E, Lees RD, Hoban K, Sleigh JN, Zhou H, Muntoni F, Talbot K, Gillingwater TH, Parson SH. Ann Neurol. 2016 Feb;79(2):217-30.
2. Survival Motor Neuron (SMN) protein is required for normal mouse liver development. Szunyogova E, Zhou H, Maxwell GK, Powis RA, Muntoni F, Gillingwater TH, Parson SH. Sci Rep. 2016 Nov 10;6:35898.
3. Survival of motor neurone protein is required for normal postnatal development of the spleen. Thomson AK, Somers E, Powis RA, Shorrock HK, Murphy K, Swoboda KJ, Gillingwater TH, Parson SH. J Anat. 2017 Feb;230(2), 337-346.
4. UBA1: At the crossroads of Ubiquitin Homeostasis and Neurodegeneration. Groen EJN and Gillingwater TH. Trends in Mol Med. 2015 Oct;21(1) 622-632.
5. Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function. Smith GA, Fearnley GW, Abdul-Zani I, Wheatcroft SB, Tomlinson DC, Harrison MA, Ponnambalam S. Biol Open. 2017 15;6(10), 1404-1415.
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