About the Project
Spinal muscular atrophy (SMA) is a disease that primary causes loss of motor neurons and atrophy of muscle tissue. However, not all tissues are equally affected by pathology (Thomson et al, 2012; Ling et al, 2012; Boyd et al, 2016). The molecular basis of this selectively is not yet fully understood and in this project we would like to explore the contribution that histone modifications make to this selectivity.
Sets of epigenetic modifications (for example trimethylation at lysine 4 and acetylation of histone 3) play a crucial role in mediating cell fate and are known to be associated with differences between fast and slow twitch muscles (Kawano et al, 2015). Further, several histone deactylases (HDACs) have been implicated in muscle atrophy and dysfunction (Walsh et al, 2015). HDAC inhibitors have been used in a number of clinical SMA studies and have been shown to improve specific neuromuscular outcomes.
This project will characterise the histone signatures of both vulnerable and resistant tissues (both muscle and motor neuron derived). It will also investigate the therapeutic potential of specific HDAC inhibitors. Data from this project will be relevant to the SMA field, but also of potential interest to researchers of muscular dystrophies and motor neuron diseases.
Prerequisites
Background: Basic neuroscience, molecular biology, genetics
Skills: General laboratory experience, including quantitative assays, DNA/protein handling
Funding Notes
This studentship is funded by the Euan MacDonald Centre for MND Research: http://www.euanmacdonaldcentre.com/training/. It includes the standard provision of:
• Stipend for three years
• UK/EU University fees
• Oversight by a second supervisor & thesis committee
• Access to all training & support available to postgraduates at the chosen University
References
1) Boyd PJ, Tu W-Y, Shorrock HK, Groen EJN, Carter RN, Powis RA, Thomson SR, Thomson D, Graham LC, Moytl AAL, Wishart TM, Highley JR, Morton NM, Becker T, Becker CG, Heath PR, Gillingwater TH. (2017) Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy. PLoS Genetics 13(4) e1006744
2) Kawano F, Nimura K, Ishino S, Nakai N, Nakata K, Ohira Y. (2015) Differences in histone modifications between slow- and fast-twitch muscle of adult rats and following overload, denervation, or valproic acid administration. Journal of Applied Physiology 119:p1042-1052
3) Ling KKY, Gibbs RM, Feng Z, Ko C-P. (2012) Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Human Molecular Genetics 21 (1) p185-195
4) Thomson SR, Nahon JE, Mutsaers CA, Thomson D, Hamilton G, Parson SH, Gillingwater TH. (2012) Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy. PLos One 7 (12) e52605
5) Walsh ME and van Remmen H (2016) Emerging roles for histone deacetylases in age-related muscle atrophy. Nutrition and Healthy Ageing 4 p17-30
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