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MRC DiMeN Doctoral Training Partnership: Replacing deficient microglia in the developing brain: using a zebrafish model of human leukodystrophy to test new therapies


Project Description

RNASET2-deficient leukodystrophy is a heritable white matter disorder affecting infants and characterised by severe psychomotor impairments. This disease mimics congenital cytomegalovirus brain infection, suggesting a foetal and immune origin of the disease. Animal models of leukodystrophy are rare and murine models do not recapitulate the key neuropathology of the human disease. The primary supervisor has published the first zebrafish model of this human leukodystrophy. Our rnaset2 zebrafish mutant displays white matter and locomotion defects, therefore placing this model at the forefront of pre-clinical models to test therapies for this devastating disease. We recently identified the immune cells of the brain - microglia – as early contributors to the disease, displaying profound abnormalities and failing to clear developmental apoptosis with subsequent loss of brain integrity assessed by behaviour tests and MRI.

We hypothesise that replacing deficient microglia can offer a therapeutic approach for RNAseT2-deficient leukodystrophy.

Unpublished work by the primary supervisor has developed a macrophage transplantation protocol using zebrafish. We demonstrated that transplanted macrophages from adult zebrafish can populate the brain and differentiate into microglia-like cells: expressing microglia specific markers and able to ingest apoptotic neurons. The aims of this cross-disciplinary project are to optimise and characterise the best graft to perform microglia replacement using RNA sequencing (quantitative) and imaging (qualitative) approaches. Once optimised, the transplantation will be used to test rescue of brain integrity in the rnaset2 mutant zebrafish using our validated behaviour and MRI assays.

This exciting macrophage transplantation is the first protocol to demonstrate functional replacement of microglia in the developing brain. Despite disease severity—like many leukodystrophies—RNaseT2-deficient leukodystrophy remains without treatment. However, a growing body of research has begun to explore stem cell transplantation in other leukodystrophies and immunodeficiencies, with clinical trials indicating early success. Macrophage replacement will offer a quicker and more direct route to replace deficient microglia in leukodystrophies.

We are a team of international experts in the field of neurological disorders comprised of 2 basic and 3 clinical researchers. The student will be fully trained at using zebrafish as an in vivo model, including molecular biology and microscopy. RNA sequencing will be followed by bioinformatics and quantitative PCR to provide basic training in biomedical informatics research.

You should possess a high 2.1 or 1st class degree in a relevant biological degree. Laboratory experience is desirable.

Supervisors:
Dr Noémie Hamilton (https://www.sheffield.ac.uk/iicd/profiles/hamilton)
Dr Andy Grierson (https://www.sheffield.ac.uk/neuroscience/staff/grierson)
Prof. Steve Renshaw (https://www.sheffield.ac.uk/iicd/profiles/renshaw)
Dr Christopher Duncan (https://www.ncl.ac.uk/icm/people/profile/christopherduncan.html#background)
Prof. Sophie Hambleton (https://www.ncl.ac.uk/icm/people/profile/sophiehambleton.html#background)

For enquiries about the project please contact Dr Noemie Hamilton


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 can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Noémie Haud (Hamilton), Kara F, Diekmann S, Henneke M, Willer JR, Hillwig MH, Gregg RB, MacIntosh GC, Gärtner J, Alia A, and Hurlstone A. RNase T2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA. PNAS 2011.

Noémie Hamilton, Holly A. Rutherford, Hannah M. Isles, Jessica J Petts, Marco Henneke, Jutta Gärtner, Mark Dunning, Stephen A Renshaw. Failure to clear developmental apoptosis contributes to the pathology of RNASET2-deficient leukoencephalopathy. bioRxiv doi.org/10.1101/744144.

Holly Rutherford and Noémie Hamilton. Animal Models of Leukodystrophy: A new perspective for the development of therapies. doi:10.1111/febs.15060.

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