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MRC DiMeN Doctoral Training Partnership: Genetic epilepsy: identifying mechanisms and potential drug treatments, from nematodes to humans


MRC DiMeN Doctoral Training Partnership

Liverpool United Kingdom Genetics Molecular Biology Neuroscience Pharmacology Physiology

About the Project

Epilepsy is a common neurological disorder that has a major impact on patient mortality, morbidity and quality of life. Clinical management remains extremely problematic, held back both by diagnostic and treatment limitations. Around 40% of cases are considered to be “genetic epilepsy” (~250,000 people in UK), but often, the identity of the genes involved eludes us. However, a recent landmark paper has identified mis-sense mutations in GABAA receptors as a common cause of genetic epilepsy (Lancet Neurology (2018) 17, 699). This presents a timely opportunity to understand how these mutations in GABAA receptors lead to epilepsy and to translate this knowledge into much needed new therapies (around 1/3 of epileptics are resistant to current medication).
Our novel project combines the simple molecular genetics of the nematode worm, C. elegans, with the translational power of electrophysiological recording from mammalian neurons, to identify potential new antiepileptic drugs. This capitalises on the different expertise of the supervisory team in C. elegans disease models (Morgan, Barclay) and rodent and human brain slice electrophysiology (Trevelyan, Ilie).
The Morgan/Barclay labs have developed a humanised worm approach, where C. elegans genes are mutated and replaced with wild type or epilepsy-associated human genes (Reference 1). In this project, we will use CRISPR to knock out the C. elegans unc-49 gene, which encodes a worm GABAA receptor. We have recently demonstrated that mutations in unc-49 cause seizure-like behaviour in C. elegans and used this to identify a novel anti-epileptic drug that stimulates GABAA receptors in worms, fish, mice and humans (Reference 2). By expressing either wild type or epilepsy-associated human mutant GABAA receptors in the unc-49 knockout worms, this simple method will identify mutations that impair human GABAA receptor function, since these will be less effective at rescuing the unc-49 seizure phenotype. Worms expressing defective GABAA receptor responses will then be screened using known GABAergic drugs and novel compounds to identify potential new treatments.
We will then test the efficacy of these identified candidate drugs in simple assays of cortical network function perfected by Trevelyan and Ilie, using rodent and human brain slices. These assays have been developed from extensive in vitro studies, that have been validated as representative of the activity patterns also seen in vivo, of spontaneous, medically-refractory epilepsy in humans (Reference 3). This work will rigorously test the translational potential of candidate drugs, thereby priming future clinical trials. Indeed, the Ilie/Trevelyan collaboration has recently shown that the new anticonvulsant we identified as a GABAA receptor modulator in nematode worms works in exactly the same way in mouse and human brain slice models (Reference 2).
Importantly, this Studentship will provide unique research training in epileptology, using state-of-the-art techniques in molecular genetics, pharmacology and electrophysiology, and giving experience in model systems ranging from nematode worms through rodents to the human brain.


Supervisor web sites:
Supervisor 1, Alan Morgan (Liverpool):
https://www.liverpool.ac.uk/translational-medicine/staff/alan-morgan/

Supervisor 2, Jeff Barclay (Liverpool):
https://www.liverpool.ac.uk/translational-medicine/staff/jeff-barclay/

Supervisor 3, Andrew Trevelyan (Newcastle):
https://www.ncl.ac.uk/ion/staff/profile/andrewtrevelyan.html#background

Supervisor 4, Andrei Ilie (Newcastle):
https://loop.frontiersin.org/people/598163/overview

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:
https://bit.ly/3lQXR8A


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website

Studentships commence: 1st October 2021

Good luck!

References

1. Zhu. B., Mak, J.C.H., Morris, A.P., Marson, A.G., Barclay, J.W., Sills, G.J. and Morgan, A. (2020) Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanised Caenorhabditis elegans. Epilepsia 61, 810-821.

2. Jones, A., Barker‐Haliski, M., Ilie, A.S., Herd, M.B., Baxendale, S., Holdsworth, C.J., Ashton, J.P., Placzek, M., Jayasekera, B.A.P., Cowie, C.J.A., Lambert, J.J., Trevelyan, A.J., White, H.S., Marson, A.G., Cunliffe, V.T., Sills, G.J. and Morgan, A. (2020) A multi-organism pipeline for antiseizure drug discovery: Identification of chlorothymol as a novel γ‐aminobutyric acidergic anticonvulsant. Epilepsia in press https://doi.org/10.1111/epi.16644.

3. Schevon, C.A., Weiss, S., Goodman, R.R., McKhann, G., Jr. Emerson, R.G., Trevelyan, A.J. (2012) Evidence of an inhibitory restraint of seizure activity in humans. Nature Communications 3, 1060.

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