Type I interferons (IFN-I) are best known as antiviral cytokines (1). They also have potent immunological effects. Tight regulation of IFN-I activity is crucial for homeostasis (1). The brain is especially vulnerable to perturbations of this pathway. Recently our group discovered a novel genetic defect of IFN-I regulation (2). Early onset neurological disease was a prominent feature. This is reminiscent of a set of disorders termed type I interferonopathies (3).
Understanding how IFN-I causes neurological disease is a fundamental challenge. There are many questions. What is the timing of onset? Is disease intrinsic to the brain or secondary to systemic effects? What brain cell types drive pathology? Can it be reversed? Drugs targeting the IFN-I pathway are becoming available. IFN-I is also implicated in Alzheimer’s disease and other common neurodegenerative states. The answers are relevant to many human diseases, informing treatment decisions for patients.
Few type I interferonopathy animal models manifest neurological disease. This has been a barrier to progress in the field. We have addressed the gap with a CRISPR/Cas9 knock-in mouse model. It recapitulates key features of human pathology, including neurological disease (manuscript in preparation). This is an exciting development for various reasons. It suggests that IFN-I is causal of neuropathology. It provides a platform to study IFN-I mediated disease and test new treatments. Yet the questions listed above remain.
To address these questions, we have generated a conditional knock-in mouse model. We will use this to target specific brain cell types, at different stages of development. A range of behavioural and histopathological analysis methods are established in the laboratory. These will be applied to the conditional mutants. Complementary in vitro models are also available, to dissect molecular mechanism(s). These include:
(i) murine and human organotypic brain slice cultures
(ii) neurones and microglia derived from patient-derived pluripotent stem cells.
References:
1. Trends in Genetics (2020) S0168-9525(20)30231-6. doi: 10.1016/j.tig.2020.08.017
2. Science Immunology (2019) 13;4(42):eaav75013.
3. Annual Review of Immunology (2019) 37:247-267.
Training and opportunities:
You will emerge with a unique skillset in neuroimmunology. This includes cutting-edge techniques relevant to a broad range of biomedical disciplines:
1. Whole organism physiology
2. Molecular neuroanatomical approaches including neural tracing, immunohistochemistry
3. Pluripotent stem cell disease modelling
The multidisciplinary supervisory team comprises experts in innate immunity, immunogenomics and neuroscience. You will access purpose-build facilities and opportunities for mentorship from world-leading scientists. Research findings will be communicated at regular internal seminars and external conferences. Our previous DIMEN students have a strong track record of high impact journal publications, conference presentations and doctoral research prizes.
Supervisory team:
Dr Christopher Duncan
https://www.ncl.ac.uk/medical-sciences/people/profile/christopherduncan.html
@chrisjaduncan
Dr Gavin Clowry
https://www.ncl.ac.uk/medical-sciences/people/profile/gavinclowry.html
Professor Sophie Hambleton
https://www.ncl.ac.uk/medical-sciences/people/profile/sophiehambleton.html
Dr Lei Huang
https://www.ncl.ac.uk/medical-sciences/people/profile/leihuang.html
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 and how to apply can be found on our website:
https://bit.ly/3lQXR8A
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