How does inflammation leading to scarring differ from inflammation resolving without scars?


   Leeds Institute of Molecular Medicine

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  Dr M Wittmann, Dr E Vital  No more applications being accepted  Competition Funded PhD Project (European/UK Students Only)

About the Project

Supervisors: Dr Miriam Wittmann (UoL & Centre of Skin Sciences, UoB), Dr Ed Vital (Rheumatology, UoL), Mr Mark Goodfield (Dermatology, UoL)

Clinical significance: We currently lack therapeutic approaches to prevent scarring in inflammatory responses associated with lupus erythematosus or scarring subtypes of acne. There is a significant clinical need for therapeutic approaches which can prevent a scarring outcome of inflammatory responses.

Most inflammatory skin diseases heal without scars. There are, however, exceptions such as lupus erythematosus (LE), acne and lichen planus. All these diseases show scarring and non-scarring phenotypes and scars occur predominantly in the face and / or scalp where they lead to permanent hair loss. Once the tissue has scarred, there is no treatment to reverse this process. Furthermore, prevention of scarring is difficult, even in those diagnosed early. This is a fundamental shortcoming in our dermatological therapy.

The key differences in the inflammatory response which lead to either scarring or non scarring outcome are elusive to date. Interestingly, psoriasis, a common skin disease characterised by hyperproliferation in the epidermal compartment does not scar despite existing barrier defects. The latter disease is characterised by high levels of IL-17 and IL-22 in the inflamed tissue.

Our investigation is based on preliminary data and the hypothesis that intrinsic differences in patient tissue responses impact on how inflammatory damage is repaired. There is strong evidence for IL-22 playing a beneficial role in skin repair. This repair response may be tipped to defect healing with scarring in the presence of high levels of interferons (IFN) which inhibit cell proliferation and angiogenesis. We will focus our investigation on the functional impact of the hypothesised dysbalance between IFNs and IL-22 and their opposing roles in skin repair using cells and tissue from patients with scarring and non-scarring phenotypes of the above mentioned diseases and as a control from patients with psoriasis or healthy subjects.

The plan of investigation covers (1) the analysis of phenotype, growth and differentiation of patient derived skin cells; (2) the analysis of tissue cell crosstalk (epidermo-mesenchymal) with regard to cell growth and soluble mediator production in scarring and non-scarring disease phenotypes and (3) the detection of differences in the cytotoxic function of patient derived skin homing lymphocytes.

In this study, we will combine the skills and knowledge of clinicians and immunologists in the field of LE, wound healing, hair follicle biology, and cutaneous cytokine network.

Delivery: We aim to suggest improved therapeutic approaches for early intervention in scarring skin diseases. We will deliver a rationale for scar prevention approaches e.g. based on existing and emerging drugs interfering with specific Jak/Stat pathways, with innate IFNs or approaches aiming to regulate endogenous binding proteins (e.g. IL-22BP, IL-18BP). Results from this project will be of high importance to direct future specific therapeutic developments aiming to prevent defect healing.

Funding Notes

Studentships are available from February 2013 for a fixed term of 3 years. Each studentship will fund EU/Home tuition fees, a stipend at MRC rate and laboratory consumables.

Applicants should hold a relevant first degree at a standard of 2:1 or above and are encouraged to contact the appropriate supervisor to discuss the project before submitting their application by Monday 26th November 2012.

Candidates invited to attend the interview day, on Tuesday 11th December 2012, will have the opportunity to meet supervisors and to discuss projects in more detail. Candidates will also be shown around LIMM facilities and meet staff from the different Divisions. Candidates invited for interview will be informed by Monday 3rd December.

Applications should include a covering letter choosing up to 2 projects (see link below for more details) the applicant may want to be considered for, a full CV and full details of 2 academic referees.

Additional

Applicants are requested to consider the 6 projects outlined here and indicate an interest in up to 2 projects.

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