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Pyroptotic and inflammatory effects of Staphylococcus aureus on skin epithelia in atopic dermatitis (eczema)

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  • Full or part time
    Dr Arkwright
    Dr Pennock
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

A quarter of children in the UK suffer from atopic dermatitis (eczema), which is linked to the subsequent development of asthma and food allergies. Secondary bacterial skin infection with Staphylococcus aureus (SA) is a key trigger. Our laboratory is unravelling the mechanism by which SA triggers the inflammatory response in skin cells - which forms the basis for this PhD.

We have shown that:

(i) live SA induces pyroptosis and release of IL-33 via a serine protease-dependent pathway in both mouse and human cells.
(ii) IL-33 release is blocked by commensal skin bacteria, suggesting that an imbalance in the skin microbiome drives disease.
(iii) In an NC mouse model of spontaneous AD skin cells are unable to control IL-33 activity because of lack of production of a soluble decoy receptor, supporting a role for IL-33 in disease.

Our hypothesis is that serine proteases produced by live SA drives pyroptosis and a pro-inflammatory cytokine IL-33, triggering clinical disease.

The main objectives of the study are:

- To precisely define the cellular mechanisms by which live SA induce their pathogenic effects in human and mouse epithelia
- To understand how commensal bacteria block the pathogenic effects of live SA
- To translate findings to a mouse NC/Tnd model and human skin tissue model

The successful candidate will apply various methods to establish these objectives, including accessing clinical sample collections, growth of human keratinocytes, skin tissue model and competitive studies with pathogenic and non-pathogenic bacteria, immunological assays and ex vivo culture.

The data generated holds potential for developing novel therapeutics (ST2 analogues and bacterial products) for atopic dermatitis in children.

The project will be conducted within the Institute of Inflammation and Repair, one of the UK’s leading centres for inflammation research. The successful candidate will benefit from training in cell culture, gene manipulation, immunology, bacterial culture, and the potential to oversee clinical application.

Candidates are expected to hold a minimum upper-second (or equivalent) undergraduate degree in a related biomedical/biological science such as microbiology, cell biology, immunology. A Masters qualification in a similar area would be a significant advantage as would previous experience of cell culture, ELISA, FACS analysis, and gene manipulation.

This 3-year full-time PhD is open to candidates able to provide evidence of self-arranged funding/sponsorship. Annual fee rates for this project, due to commence from July 2016 onwards, are:

*UK/EU nationals: £18, 500
Non-EU nationals: £31, 500

There is potential to commence the study in early-2016 if this suits the successful candidate.

Please direct applications in the following format to Dr Peter Arkwright, [email protected]

• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date
• Evidence of funding

Any enquiries relating to the project and/or suitability should be directed to Dr Arkwright. Applications are invited on an on-going basis but early expression of interest is encouraged.

http://www.inflammation-repair.manchester.ac.uk/staff/PeterArkwright
http://www.inflammation-repair.manchester.ac.uk/

Funding Notes

*UK/EU tuition fees are subject to an annual inflationary increase, anticipated to be approximately 2.5% p.a.

References

1. Jang J, . . . Arkwright PD, . . . Tanaka A. Skin pH is the master switch of kallikrein 5-mediated skin barrier destruction in a murine atopic dermatitis model. J Invest Dermatol, 2015 (in press).

2. Martin E, et al (Arkwright PD joint senior author). CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature 2014;510:288-92.

3. Assas BM, Miyan JA, Pennock JL. Cross-talk between neural and immune receptors provides a potential mechanism of homeostatic regulation in the gut mucosa. Mucosal Immunol 2014 Sep 3.

4. Mohammedsaeed W, McBain AJ, Cruickshank SM, O'Neill CA. Lactobacillus rhamnosus GG Inhibits the Toxic Effects of Staphylococcus aureus on Epidermal Keratinocytes. Appl Environ Microbiol 2014;80:5773-81

5. Prince T, McBain AJ, O'Neill CA. Lactobacillus reuteri protects epidermal keratinocytes from Staphylococcus aureus-induced cell death by competitive exclusion. Appl Environ Microbiol 2012;78:5119-26.

How good is research at University of Manchester in Clinical Medicine?

FTE Category A staff submitted: 136.18

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