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CENTRE FOR CUTANEOUS RESEARCH
Barts and London School of Medicine and Dentistry, Queen Mary, University of London.
www.smd.qmul.ac.uk/cutaneous/

The Centre for Cutaneous Research (CCR) is composed of the Academic Department of Dermatology and the Cancer Research UK (CRUK) Skin Tumour Laboratory. The CCR has close links with the Clinical Department of Dermatology at the Royal Hospitals Trust and is one of the largest academic dermatology departments in Europe. In addition to providing a significant clinical service for both general and specialist dermatology, it teaches core curriculum in undergraduate studies.

The focus of research on the cellular and molecular biology of human skin and associated diseases. We will be moving into a purpose built multidisciplinary research centre, namely the Institute of Cells and Molecular Science, due for completion by April 2004. A lab management committee of senior academics provides the management structure of the department chaired by Harshad Navsaria. External funding of around £1.5million is obtained yearly.
Research within the department is currently organised into distinct programmes that bring together a critical mass of clinical and non-clinical researchers. Specific research themes are:

(a) keratinocyte biology,
(b) tissue engineering and wound healing, and
(c) non-melanoma skin cancer.

Keratinocyte Biology

The epidermis is an ideal model organ to understand the cellular and molecular mechanism of cell differentiation and proliferation. Current studies include investigating protein-protein interactions between keratins and desmo-somal junctions and the role of connexins in gap junctional intercellular communication. In addition, we have an active disease gene-mapping programme. These studies have resulted in a number of landmark findings including the identification of connexin 26 mutations as the major cause of genetic deafness worldwide. The possibility of gene therapy is also being explored, such as the replacement of normal genes into keratinocytes from patients with hereditary recessive epidermal fragility disorders. We currently have an active research programme using the hair follicle as a model to investigate the role of growth and transcription factors in regulating epithelial-mesenchymal interactions and stem cell fate during embryogenesis and the hair cycle.

Non melanoma skin cancer (NMSC)

NMSC is the most common cancer. Current research focuses on the investigation of the mechanisms in which viral oncoproteins from cutaneous HPV types interact with known cellular proteins. These studies have resulted in key findings including the genetic and functional association of P53 polymorphisms with cancer susceptibility and progression. In a separate programme of research we are investigating the role of developmental genes including the hedgehog and Wnt signalling pathways in the development of basal cell carcinomas.

Tissue Engineering and Wound Healing

Background

Over the past two decades extraordinary advances in tissue bioengineering, cellular and molecular biology have led to a greatly improved comprehension of the basic biological processes involved in tissue replacement, regeneration and repair.

Cultured keratinocytes have been successfully applied in a variety of skin defects with mixed results. Keratinocytes grafted onto full-thickness wounds in the absence of dermis result in skin fragility, blistering and formation of hypertrophic scar. There is a major medical need for an effective dermal replacement, as dermal tissue does not regenerate into normal dermis in vivo after serious burns; instead dermal tissue potentiates the formation of scar tissue.

Using tissue engineering, researchers have developed in vitro skin substitutes comprising of both epidermis and dermis which are currently being clinically evaluated and may replace many toxicological tests currently performed on animals and humans. Ultimately strides in basic knowledge will lead to advancements in wound care resulting in accelerated rates of chronic and acute wound repair, scars of greater strength, and prevention of keloids, hypertrophic scarring and fibrosis.

This information might translate into a better design of artificial organs and tissue substitutes since the exposed surfaces of these materials should be designed so that they elicit either no response or a strong, stable union with the surrounding tissue. Important advances in understanding growth factors and how to provide scaffolding for engineered cells are critical for converting the promise of this exciting field into potential benefits.

From left to right: Matthew Griffiths, Kem Ojeh,
Harshad Navsaria and Mark Goulder

While these goals have not been achieved, new scientific facts continue to accumulate at an accelerating pace. Clearly today's scientific breakthroughs in the processes of wound healing and tissue regeneration will lead to tomorrow's therapeutic successes in wound care and tissue engineering.

There is a need for rapid epithelialisation of the skin following burn injury or surgery to prevent infection. Our current research focuses on novel substrates (biopolymers) for tissue engineering: de-epidermalised dermis, collagen and derivatives of hyaluronic acid. We have developed in vitro (organotypical), animal (porcine chamber) and human (tattoo excision) models. In addition to the clinical application of tissue engineered skin in various pathologies, these models are also used within the department, as well as in vitro models of epidermal differentiation to study the biology of human papillomavirus, the regulation of gene expression and tumorigenesis. Research is also being carried out to develop in vitro models that support embryonic development of the skin and its glands and appendages. A new programme identifying key molecules involved in keratinocyte migration has been established which will complement the current studies.

Research objectives

• To develop a laboratory grown, permanent skin replacement with minimal donor site for the treatment of wounds that result from the failure of cutaneous protective mechanisms, i.e., large burn injuries and chronic wounds.
• To increase the rate of healing in skin injuries that do not affect the full thickness of the skin, and minimise the scarring that results from normal repair mechanisms.
• To understand the interactions of epithelial cells with their supporting tissue during development and in the adult, towards the production of whole organs for transplantation (epithelial / mesenchymal interactions).
• To understand the role of allogenic keratinocytes and fibroblasts in acute and chronic wounds.
• To develop in vitro systems for the study of carcinogenesis and toxicology that do not involve animals.
• To optimise keratinocyte transfection systems to label keratinocytes, or to modify keratinocyte phenotype.
• To understand adult keratinocyte stem cell biology and embryonic stem cell differentiation into skin.

Group Leaders
Director of Laboratory: Irene Leigh
Tissue Engineering/Wound Healing: Harshad Navsaria
Hair Biology: Mike Philpott
Genetic Disorders: David Kelsell
Keratin Disorders: Liz Rugg
Human Papiloma Virus: Alan Storey (CRUK)
Cell Migration: Edel O'Toole
Clinical Research: Catherine Harwood, Charlotte Proby and Jane McGregor