Background: A quarter of children in the UK suffer from atopic dermatitis (eczema). One in 20 have severe disease not responsive to topical treatment. Injectable biologics have recently been licenced for treatment of severe disease. We have recently discovered that currently licenced oral protease inhibitors (PI) used to treat HIV and viral hepatitis block IL-33 release from the skin triggered by Staphylococcus aureus, a bacteria associated with atopic flares. However the mechanism by which these PI work is unclear.
Objectives: To determine the efficacy and mechanism of action of commercially available PI in blocking the release of IL-33.
Methods: We aim to develop a IL-33 assay using system microscopy to monitor movement of this constitutive nuclear cytokine from the nucleus to the external mileu in live cells after bacterial stimulation. This builds on established molecular methodology here at the University of Manchester. Both chemical and pharmaceutical PI will then be tested in our primary keratinocyte in vitro model. The inhibitory effect of PI on translocation of IL-33 from the nucleus to the external milieu will also be explored. Inhibition of cytoplasmic cell signalling and other factors e.g. polymerase I & transcript release factor (PTRF) and cytochromic P450 components will be studied using specific inhibitors and siRNA knockdowns. In vitro results will then be translated into our in vivo mouse models currently available (NC/Tnd mice available via collaborators in Tokyo, Japan) and the flaky tail model of AD at the University of Manchester being developed as part of our current MRC project grant.
Potential outcome/impact: The short-term impact is a better understanding of key pathways involved in blocking IL-33 release from skin cells, a key early driver of atopic dermatitis. The medium to long-term impact is to repurpose currently available, licenced, therapeutic PI in the treatment of severe allergic skin disease, with potential additional translation to related conditions such as asthma.
https://www.bmh.manchester.ac.uk/research/domains/infection-immunity-inflammation-repair/immunology/life-course-immunology/
https://www.research.manchester.ac.uk/portal/peter.arkwright.html
https://www.research.manchester.ac.uk/portal/joanne.l.pennock.html
https://www.research.manchester.ac.uk/portal/andrew.mcbain.html
Entry Requirements
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
How to Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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