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Investigating the pathophysiology of Motor Neuron Disease (MND/ALS) using rodent and human iPSC-based models


Project Description

There is growing evidence that early changes in neuronal function contribute to the pathogenesis of Motor Neuron Disease/Amyotrophic Lateral Sclerosis (MND/ALS). Early dysfunction in ALS is characterised by changes in the ability of motor neurons to convert synaptic input into appropriate action potential output for muscle activation. However, the mechanisms that underlie this change in motor neuron excitability and its downstream effects on motor neuron survival remain unclear. This project therefore aims to: reveal which specific ion channels (or other membrane proteins) contribute to altered motor neuron excitability in ALS; determine the effects of manipulating (up and down) the excitability of healthy and ALS-affected motor neurons; and investigate the actions and potential benefits of agents that can modulate the membrane proteins found to underlie changes in motor neuron excitability in ALS. These aims will be addressed by utilising a range of physiological (e.g. patch-clamp electrophysiology, live calcium imaging) and molecular techniques applied to cutting-edge human induced pluripotent stem cell (iPSC) and animal-based models of ALS. We expect to reveal important insights into disease mechanisms and highlight targets for new treatment strategies for this devastating disease.

Funding Notes

This project is offered as part of the SPRINT-MND/MS PhD Programme and covers tuition fees and provides a stipend. You should apply directly to the University of St Andrews in accordance with the process outlined at: View Website

Informal inquiries to the primary supervisor, Prof Gareth Miles, are very strongly encouraged.


References

A.C. Devlin, K. Burr, S. Borooah, J. D. Foster, E. M. Cleary, I. Geti, L. Vallier, C. E. Shaw, S. Chandran and G. B. Miles (2015). Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nature Communications, 6:5999 doi:10.1038/ncomms6999.

Thangaraj Selvaraj , B. , Livesey , M. , Zhao , C. , Gregory , J. , James, O. , Cleary, E. , Chouhan, A. K. , Gane, A. , Perkins, E. , Dando, O. , Lillico, S. , Lee, Y. , Nishimura, A. , Poreci, U. , Thankamony, S. , Pray, M. , Vasistha, N., Magnani, D. , Borooah, S. , Burr, K. Story, D., McCampbell, A., Shaw, C., Kind, P., Aitman, T., Whitelaw, B., Wilmut, I., Smith, C., Miles, G. B., Hardingham, G., Wyllie, D. & Chandran, S (2018). C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+ -permeable AMPA
receptor-mediated excitotoxicity. Nature Communications, 9(1):347. doi:10.1038/s41467-017-02729-0.

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