Dr S Pulver
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Alterations in TAR DNA-binding protein 43 (TDP-43) expression in neurons and glia is associated with neurological symptoms observed in Amyotrophic Lateral Sclerosis (ALS). In a Drosophila model of ALS, manipulation of TDP-43 expression in glia leads to degeneration of neuromuscular junctions (NMJs) (1). In these experiments, both anatomical features of the larval NMJ (including glutamate receptor clustering) and the frequency of larval locomotor rhythms were affected (2,3). The physiological consequences of these changes in glutamate receptor clustering have yet to be fully investigated at the level of individual synaptic release sites. Furthermore, the observed change in locomotor frequency strongly suggests that central pattern generating (CPG) networks are modulated, but this link has yet to be explored. The objective of this project is to examine how manipulating expression of DNA-binding proteins such as TDP-43 in glia modulates i) release of transmitter at single synaptic release sites at NMJs in larval Drosophila and ii) the activity of CPG networks controlling larval locomotion. Using the GAL4-UAS and LexA-LexAOP systems, we will start by manipulating TDP-43 gene function in glia while simultaneously employing genetically encoded calcium indicators to measure calcium transients at individual release sites at the NMJ (4) and CPG activity in central circuits (5). This work will enhance our understanding of the interplay between glial cell function and the aetiology of ALS. Critically this project will focus on establishing high throughput assays for optically measuring activity in Drosophila ALS models. This novel approach will help pave the way for increased use of Drosophila as a screening platform to uncover links between glial function and the progression of motor neuron disease.
Prerequisites
Suitable students will have an undergraduate degree in neuroscience or biology and will have shown an aptitude for conducting independent research. Knowledge of Drosophila genetics, ALS disease models and/or live imaging would also be desirable.
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) Ince P.G., et al. (2011) Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol.v122:657–671.
2) Diaper D.C.,et al. (2013) Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD. Hum. Mol. Genet. 22, 3883–3893.
3) Romano et al., Glial TDP-43 regulates axon wrapping, GluRIIA clustering and fly motility by autonomous and non-autonomous mechanisms. Hum Mol Genet. (2015) 24(21):6134-6145.
4) Melom J.E., et al. (2013) Spontaneous and evoked release are independently regulated at individual active zones. J. Neurosci. 33:17253–17263.
5) Pulver S. R. et al. (2015) Imaging fictive locomotor patterns in larval Drosophila. Journal of neurophysiology 114, 2564–2577
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