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Construction of functional in vitro human spinal cord circuits for neurodegenerative disease research


Neuroscience Institute

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Dr A Tsakiridis , Dr M Livesey No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Sheffield United Kingdom Cell Biology Genetics Medical Physics Neuroscience

About the Project

Spinal circuits are comprised of both central system (CNS) and peripheral nervous system (PNS) components and functionally unify to underpin proper locomotor and sympathetic nervous system function. These circuits also represent the primary substrate for many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). The in vitro generation of spinal cord cell types from human pluripotent stem cells (hPSCs) is an attractive strategy for the development of disease modelling and regenerative medicine applications and is a major focus of our laboratories. The advent of organoids, 3-dimensional (3D) self-organising structures arising from hPSC aggregates, has further revolutionised reverse cell engineering strategies by offering a platform for producing a wide range of neural cell types in a highly regionalised manner. This approach has the potential to recapitulate cell-cell interactions and neuronal circuit formation providing novel opportunities to model both development and disease1. A number of recent studies have reported the successful derivation of spinal cord organoid systems, however, all published protocols to date do not fully recapitulate the highly clinically relevant CNS-PNS circuit along the anteroposterior (A-P) axis. The proposed project aims to generate organoids corresponding exclusively to specific CNS regions of the A-P axis that functionally incorporate efficiently neural crest (NC)-derived components of the PNS – an area of work that has been the primary focus of the Tsakiridis group2-4 (https://www.tsakiridislab.com/).

To further exploit this new system in the context of disease modelling, we will utilise it to investigate circuit dysfunction in the context of ALS, given its heterogeneous impact upon the A-P axis. The student will first define the optimal conditions for the in vitro generation of CNS-PNS spinal cord organoids corresponding to various levels of the A-P axis from hPSCs. This will be followed by characterisation of regionally-defined CNS-PNS spinal cord organoids using electrophysiology/calcium imaging. Finally, the student will investigate regionally-defined CNS-PNS spinal cord organoids generated from ALS patient induced PSCs (hiPSCs) harbouring mutations causal to ALS.

Applications are open to students from both the UK and overseas, though we note that due to funding constraints the availability of positions for students with overseas fee status will be more limited. We anticipate competition for these studentships to be very intense. We would expect applicants to have an excellent undergraduate degree in a relevant discipline. We would also expect applicants to have completed or be undertaking a relevant master’s degree to a similar very high standard (or have equivalent research experience).

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Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgradapplication/

Please clearly state the prospective main supervisor in the respective box and select ‘Neuroscience’ as the department.

After the application closing date, we will shortlist applicants for an online interview. We expect to carry out interviews (each lasting approximately 30 minutes) on Tuesday 27th April (am, GMT) and Tuesday 4th May (pm, GMT). If you are shortlisted for interview, we will aim to inform you of this no later than the end of Friday 23rd April. If you are unable to attend at the specified times, please let us know if we confirm that we would like to interview you.


Funding Notes

UNIVERSITY FUNDED
• 3.5 years PhD studentship commencing October 2021
• UKRI equivalent home stipend rate per annum for 3.5 years
• Tuition fees for 3.5 years
• University of Sheffield funded studentships are supported with £3000/year for consumables.

References

(1) Lancaster MA and Hutch M. Dis Model Mech. 2019 Jul 29;12(7):dmm039347.
(2) Frith TJ et al. Elife. 2018 Aug 10;7:e35786.
(3) Frith TJ et al. Stem Cell Reports. 2020 Sep 8;15(3):557-565.
(4) Wind M et al. Development. 2021. dev.194415. doi: 10.1242/dev.194415.
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