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MRC DiMeN Doctoral Training Partnership: Use of 3D skin models and patient-derived immune cells to elucidate the molecular mechanisms of skin detachment in severe drug-induced skin adverse reactions


MRC DiMeN Doctoral Training Partnership

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Dr D Carr , Prof D Naisbitt , Prof A Dickinson No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Liverpool United Kingdom Biochemistry Molecular Biology Medicine Pathology Pharmacology

About the Project

Background:
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening skin adverse drug reactions which can be caused by a multitude of prescriptions drugs. Though rare, SJS/TEN has a high mortality rate (5-30%) and can have devastating long-term effects on survivors, including loss of vision.

SJS/TEN are immune-mediated reactions which are primarily characterised by keratinocyte death and wide-spread skin detachment. Significant research has been undertaken to understand the immunological mechanisms of SJS/TEN. However, little is understood of the pathogenesis of epidermal detachment and skin cell (keratinocyte) injury. Indeed, the reason why some individuals progress to SJS/TEN while others exhibit only mild rash-like symptoms is not known. To date, no physiologically applicable cell-based models of SJS/TEN exist with which to probe the molecular basis of the epidermal detachment. Understanding of this has the potential to identify novel therapeutic targets for the treatment of SJS/TEN. At present no targeted therapy exists.

Project description:
The project will expand on existing 2D cell-culture work by using 3D skin equivalents and human skin explants to investigate the molecular pathogenesis of epidermal detachment in SJS/TEN. This represents the first time that 3D skin models have been utilised for the purpose of SJS/TEN research.

We have identified a novel molecular pathway which is up-regulated by the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) in SJS/TEN patient skin and has a key role in the breakdown of the dermal/ epidermal junction leading to epidermal detachment/ blistering. Using SJS/TEN and healthy patient serum, and conditioned media from activated, isolated patient T-cells you will treat-exposed keratinocyte cell-lines and 3D skin-equivalents and investigate and characterise how the TNF-α molecular pathway mediates epidermal detachment. Furthermore, you will investigate how novel targeted therapies can modulate the effect of TNF-α to alleviate epidermal detachment.

Research Training and Supervision
This studentship would provide a unique training opportunity to be trained both in vitro modelling, immunological cell assays and molecular biological techniques by a highly experienced supervisory team each with complementary research skills. You will work under the supervision of Dr Dan Carr (https://www.liverpool.ac.uk/translational-medicine/staff/daniel-carr/) (@daniel_f_carr) and Prof. Dean Naisbitt https://www.liverpool.ac.uk/translational-medicine/staff/dean-naisbitt/) (@ImmunoPharm) from the MRC Centre for Drug Safety Science (@CDSS_Liverpool) a world-renowned centre of excellence for drug safety research. The student gain experience of 2D and 3D skin cell culturing and modelling techniques, immune cell activation assays and a range of molecular biology techniques including western blotting, transcriptomic analysis and immunohistochemistry. The student would also be trained in the handling and analysis of human clinical samples for the purpose of biomarker analysis.

In addition, under the supervision of Prof. Anne Dickinson you will spend up to 3 months per year working in the state-of-the-art labs of Alcyomics Ltd in Newcastle (alcyomics,com) where you will work with pre-clinical human skin biopsy models in order to apply your understanding of the mechanisms characterised in skin equivalents and gain valuable experience working in a commercial research environment.

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 and how to apply can be found on our website:
https://bit.ly/3lQXR8A

Funding Notes

iCASE Award: Industrial partnership project

Funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £17,785) only. We aim to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: https://bit.ly/3kPNjoJ

Studentships commence: 1st October 2020.
Good luck!


References

1) Carr DF, Wang CW, Bellón T, Ressel L, Nwikue G, Shrivastava V, Bergfeld W,
Jorgensen AL, Chung WH, Pirmohamed M. Serum and blister-fluid elevation and
decreased epidermal content of high-mobility group box 1 protein in drug-induced
Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol. 2019
Jul;181(1):166-174.

2) Zhao Q, Alhilali K, Alzahrani A, Almutairi M, Amjad J, Liu H, Sun Y, Sun L,
Zhang H, Meng X, Gibson A, Ogese MO, Kevin Park B, Liu J, Ostrov DA, Zhang F,
Naisbitt DJ. Dapsone- and nitroso dapsone-specific activation of T cells from
hypersensitive patients expressing the risk allele HLA-B*13:01. Allergy. 2019
Aug;74(8):1533-1548.

3) Sullivan A, Wang E, Farrell J, Whitaker P, Faulkner L, Peckham D, Park BK,
Naisbitt DJ. β-Lactam hypersensitivity involves expansion of circulating and
skin-resident T(H)22 cells. J Allergy Clin Immunol. 2018 Jan;141(1):235-249.e8.
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