Franziska Mueller was awarded a Brain Research UK PhD studentship in 2018 to enable her to pursue research in spinal cord injury.
She worked with supervisor Professor Simone Di Giovanni to take forward work that had found a way to switch on genes that stimulate limited regeneration of severed nerve fibres in the spinal cord.
Franziska was awarded her PhD from Imperial College London following successful completion of an ambitious programme of work.
The spinal cord is an extension of the brain; together they make up the central nervous system.
The spinal cord takes messages from the brain to other parts of the body, and from the body back to the brain. Damage to the spinal cord blocks these messages - much like someone drilling through a broadband cable. The ‘equipment’ either side of the injury may still be intact – the server and the router aren’t broken – but they can no longer communicate with each other.
The effect of a spinal cord injury depends on the site of the injury, and the severity of the damage. The messages get stopped from just below the site of the injury so the higher the injury, the greater the impact. Severe injuries can affect not only movement and sensation, but can also potentially affect the messages that control bowel and bladder function, breathing, heart rate and blood pressure.
The consequences are shattering. The individual – and their family – must learn to adapt to a completely new way of life, with limited function and a drastic loss of independence.
Read more: About brain and spinal cord injury
Current therapies for spinal cord injured patients are limited to neurorehabilitation. Different rehabilitative techniques aim to help the individual to rebuild their strength and regain limited physical ability, and help them develop strategies to attain a degree of independence. But there are no therapies that offer hope of repairing a spinal cord injury, to restore lost function.
Neurorehabilitation techniques take advantage of the ability of the brain and spinal cord to reorganise themselves by forming new neural connections, a process called ‘neuroplasticity’. Essentially, the nervous system tries to find new pathways when a typical route for messages is interrupted.
In the case of more severe injuries, there may simply be no alternative pathways. The old paths need to be re-established. And this was the focus of Franziska’s PhD project – her research focused on promoting the regrowth of severed nerve fibres (axons) in the spinal cord.
Working with supervisor Professor Simone Di Giovanni, Franziska built on work that had found a way to switch on genes that stimulate limited regeneration of some severed axons.
Using a mouse model of spinal cord injury, Franziska used a method known as gene therapy to insert a new gene of interest (‘Cited2’) directly into neurons. She then studied the effect of this gene to see how it actually works, and how it activates or deactivates the different cell signalling pathways that lead to axonal regeneration. She showed that overexpression of Cited2 in neurons promoted axonal regrowth after SCI, and that this was the result of adult neurons returning to a more developmental time point in which axonal regeneration is possible.
This work shows that the normal developmental loss of neuronal regenerative ability is reversible; and that repair strategies targeting neural dematuration could hold the key to repair of injuries to the central nervous system.
It is estimated that there are around 50,000 people living with a spinal cord injury in the UK, with around 1,000 new injuries occurring each year.
Rehabilitation has some benefit after moderate spinal cord injury, helping to rebuild strength, but there are no therapies that can actually repair an injury, to restore lost function. New approaches to treatment are desperately needed to improve the outlook for those affected.
Franziska’s research has added to a body of evidence showing that axonal regeneration is possible, to at least some extent, and moves us closer to the possibility of effective treatments.
Equally important, through this PhD studentship, we have helped nurture the development of a promising young researcher who we hope will go on to develop a long and illustrious career in this under-researched and under-resourced field. Franziska was awarded her PhD in February 2023 and is now continuing as a post-doctoral researcher at Imperial, aiming to identify translational opportunities stemming from her PhD research as well as broadening her scope to explore interdisciplinary approaches to axonal regeneration.
Mueller F, De Virgiliis F, Kong G, Zhou L, Serger E, Chadwick J, Sanchez-Vassopoulos A, Singh A, Eswaramoorth M, Kundu T, Di Giovanni S (2021). Combinatorial small molecule-mediated activation of CBP/p300 with environmental enrichment in chronic severe experimental spinal cord injury to enable axon regeneration and sprouting for functional recovery. bioRxiv 2021.06.07.447349; https://doi.org/10.1101/2021.06.07.447349
Müller F, De Virgiliis F, Kong G, Zhou L, Serger E, Chadwick J, et al. (2022) CBP/p300activation promotes axon growth, sprouting, and synaptic plasticity in chronic experimental spinal cord injury with severe disability. PLoS Biol 20(9): e3001310. https://doi.org/10.1371/journal.pbio.3001310
Müller, F, Chadwick, JS, Di Giovanni, S, Palmisano, I (2023). Epigenomic Profiling of Dorsal Root Ganglia upon Regenerative and Non-regenerative Axonal Injury. In: Udvadia, A.J., Antczak, J.B. (eds) Axon Regeneration. Methods in Molecular Biology, vol 2636. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3012-9_7
Acquired brain and spinal cord injury (including stroke) is one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of how to promote repair of the brain and spinal cord following injury.
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