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Mapping and Modelling Hypoxia in Spinal Muscular Atrophy


School of Medicine, Medical Sciences & Nutrition

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Prof S Parson , Dr I Fleming No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Spinal muscular atrophy (SMA) is the most common inherited cause of infant death worldwide, but there is no cure. Affected children present with a rapidly evolving pattern of disability characteristic of a motor neurone disease with loss of motor neurones from the spinal cord and muscle wasting which results in an inability to make normal movements, support posture and ultimately breath. This leads to premature death, often before the age of three. Our laboratory is at the forefront of work to understand the extent to which damage to body systems beyond the neuromuscular system drive pathology in SMA. We have shown that poor development of capillary beds leads to tissue hypoxia, and we believe that this contributes to disease pathology. This project is designed to test that idea: it involves using transgenic mouse models of severe SMA to study the expression and distribution of key markers of hypoxia including Hif1α, EPO and VEGF, using molecular and immunochemical/imaging techniques. But significantly, we will also use small animal PET imaging to map and monitor hypoxia in real-time in vivo.

This project provides an excellent opportunity to use a wide range of experimental techniques to study novel pathologies in this devastating disease.

Funding Notes

This project is funded by the Euan MacDonald Centre for Motor Neurone Disease and the School of Medicine, Medical Sciences & Nutrition, University of Aberdeen. Full funding is available to UK/EU applicants only. Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject.

References

1. Somers, E., Lees, RD., Hoban, KH., Sleigh, JN., Zhou, H., Muntoni, F., Talbot, K., Gillingwater, TH. & Parson, SH. (2016). 'Vascular defects and spinal cord hypoxia in spinal muscular atrophy'. Annals of Neurology, vol 79, no. 2, pp. 217-230.

2. Wishart, TM., Mutsaers, CA., Riessland, M., Reimer, MM., Hunter, G., Hannam, ML., Eaton, SL., Fuller, HR., Roche, SL., Somers, E., Morse, R., Young, PJ., Lamont, DJ., Hammerschmidt, M., Joshi, A., Hohenstein, P., Morris, GE., Parson, SH., Skehel, PA., Becker, T., Robinson, IM., Becker, CG., Wirth, B. & Gillingwater, TH. (2014). 'Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy'. The Journal of Clinical Investigation, vol 124, no. 4, pp. 1821-1834.

3. Somers, E., Riessland, M., Schreml, J., Wirth, B., Gillingwater, TH. & Parson, SH. (2013). 'Increasing SMN levels using the histone deacetylase inhibitor SAHA ameliorates defects in skeletal muscle microvasculature in a mouse model of severe spinal muscular atrophy'. Neuroscience Letters, vol 544, pp. 100-104.

4. Somers, E., Stencel, Z., Wishart, TM., Gillingwater, TH. & Parson, SH. (2012). 'Density, calibre and ramification of muscle capillaries are altered in a mouse model of severe spinal muscular atrophy'. Neuromuscular Disorders, vol 22, no. 5, pp. 435-442.

5. Baxter, B., Gillingwater, TH. & Parson, SH. (2008). 'Rapid loss of motor nerve terminals following hypoxia-reperfusion injury occurs via mechanisms distinct from classic Wallerian degeneration'. Journal of Anatomy, vol 212, no. 6, pp. 827-835.
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