Brain tumours are the most common type of solid tumours in children. Radiotherapy can destroy tumour cells but also damages healthy brain tissue, leading to short- and longer-term complications, including learning difficulties. These problems can worsen over time, possibly because radiotherapy may damage stem cells or progenitor cells within the brain. An important role of neural stem cells (NSCs) is to generate neuron progenitors and oligodendrocyte precursor cells (OPCs), the latter of which gives rise to mature oligodendrocytes that protect neurons by coating them with myelin. If neurons lose their myelin coating they do not function properly and may degenerate.
A new type of radiotherapy called ‘proton beam therapy (PBT)’ can reduce the severity of complications because PBT can directly target the tumour. This means that less healthy brain tissue gets exposed to radiation. Nevertheless, even with PBT, some healthy brain tissue is still irradiated, and this can affect the patient’s quality of life. Furthermore, clinicians have noted unusual neurological side-effects following PBT that are not observed with conventional radiotherapy. It is thus imperative that the mechanisms of both PBT toxicity and that of conventional photon radiotherapy are understood. Here, we will use human stem cell technology to explore the effects of conventional radiotherapy and PBT on neural stem cells and OPCs. Our long-term goal is to develop ways to protect the stem cells in the brain from radiation-induced damage.
The specific objectives are as follows:
1. Investigate effects of photon radiation and PBT on the viability and proliferation of human pluripotent stem cell (hPSC)-derived NSCs, OPCs and mature oligodendrocytes in vitro.
2. Assess the extent and type of DNA damage following in vitro exposure of NSCs, OPCs and mature oligodendrocytes to photon radiation and PBT.
3. Investigate how photon radiation and PBT affects the ability of NSCs and OPCs to differentiate into neuronal cell types and mature oligodendrocytes in vitro
4. Investigate how photon radiation and PBT affects the fate of NSCs and OPCs following implantation into the rodent brain.
The primary supervisor, Prof Patricia Murray, will provide expertise in stem cell biology; Dr Jason Parsons will provide expertise in radiobiology and DNA damage and repair; Prof Harish Poptani will provide expertise in non-invasive imaging techniques; Prof Barry Pizer will provide expertise in paediatric oncology. The Murray group also collaborates with the company, Stream Bio (https://www.streambio.co.uk/about-us/) who are developing novel imaging probes that will be used to label the cells prior to implanting them in the rodent brain so that we will be able to monitor their fate using magnetic resonance imaging and fluorescence imaging.
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, York 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:
http://www.dimen.org.uk/how-to-apply/application-overview
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