PhD Studentship: How does excessive type I interferon activity damage the brain?

Number of awards:
1

Start date and duration:
31 October 2019 for 3 years.

Overview:
Type I interferons (IFNα/β) are potent antiviral cytokines with pleotropic functions, including the regulation of cellular activation, proliferation and cell death. Intriguingly, both too little and too much IFNα/β activity is associated with neurological disease. We have previously reported loss of function mutations of this pathway in humans with severe viral disease(1, 2). We have recently discovered a novel genetic disease of uncontrolled IFNα/β signalling leading to sterile neuroinflammation. The phenotype resembles a set of genetic diseases known as type I interferonopathies(3).

Understanding precisely how IFNα/β causes neurological damage in these disorders remains a fundamental scientific and clinical challenge. This question has clinical relevance, not only because drugs targeting this pathway are increasingly available, but also because dysregulated IFN activity is implicated in common neurological diseases such as Alzheimer’s disease. A major barrier is the lack of animal models of interferonopathies that recapitulate neuropathology.

To address this need, we have generated a CRISPR/Cas9 knock-in mouse model of this novel interferonopathy mutation. Preliminary studies indicate the development of neurological disease in homozygous carriers.

Project goals:

dissect pathomechanism using cutting-edge methods of neuropathological analysis including imaging mass cytometry
exploit a new conditional knock-in mouse model, currently being generated, to determine the specific CNS cell types driving neuropathology
test novel therapeutic strategies which we are developing
Key opportunities:

You will emerge with a unique skillset in neuroimmunology, including cutting-edge experimental techniques relevant to a broad range of biomedical disciplines. The supervisory team is composed of experts in immunogenetics, innate immunity and neuroscience. Based within the Immunity and Inflammation Theme in Newcastle University, you will have access to purpose-build facilities and opportunities for collaboration and mentorship with world-leading scientists. You will also engage with a regular programme of high-quality research in progress seminars.

References:

Duncan CJ (2015) Science Translational Medicine 7(307):307ra154
Hambleton S (2013) Proceedings of the National Academy of Sciences 110(8):3053-8.
Uggenti (2019) Annual Review of Immunology 37:247-267.

Name of supervisor(s):
Dr Christopher Duncan (https://bit.ly/2F7EpRw), Professor Sophie Hambleton (https://bit.ly/2WyysDk), Professor Andrew Mellor (https://bit.ly/2Rfx7jK) and Dr Gavin Clowry (https://bit.ly/2IzUmkx).

Eligibility Criteria:
The successful candidate should possess an outstanding academic track record and be able to demonstrate their potential for development.

You must hold (or be about to obtain) a First/Upper Second Class UK undergraduate degree or an equivalent degree from a recognised EU institution, in a relevant subject (e.g. neuroscience and/or immunology). Experience of and enthusiasm for work in rodent models is highly desirable.

Please note this studentship is open to UK/EU students only.

How to apply:
You must apply through the University’s online postgraduate application system. To do this please ‘Create a new account’ (https://bit.ly/2WFPpAk).

Only mandatory fields need to be completed. However, you will need to include the following information:

insert the programme code 8300F in the programme of study section
select ‘PhD in in the Faculty of Medical Sciences (full time) – Cellular Medicine’ as the programme of study
insert the studentship code CL117 in the studentship/partnership reference field
attach a covering letter and CV no more than two pages for each. The covering letter must state the title of the studentship, quote the studentship reference code CL117 and state how your interests and experience relate to the project
attach degree transcripts and certificates and, if English is not your first language, a copy of your English language qualifications.