Developing 1600 nm OCT angiography to quantify severe inflammatory epidermal hyperplasia in atopic dermatitis

Grantee: Stephen Matcher, Professor, University of Sheffield

Amount: DKK 4,197,519

Grant category: Research grants in open competition

Year: 2021

Geography: United Kingdom

The aim of this project is to enable quantification of the effects of treating atopic dermatitis (AD) with new therapies. New therapies have similar effectiveness to steroids but are much more expensive. Thus, there is a need for demonstrated benefits and better long-term safety to persuade healthcare providers to fund them.

Optical coherence tomography (OCT) is an ideal tool to quantify the benefits of new drugs for treating AD, whilst checking that they do not cause skin thinning, which is a risk with long-term use of steroids. OCT is a non-invasive imaging technique that uses laser light to provide ultrasound-like images with higher resolution – and OCT avoids the need to perform painful biopsies.

One problem with the current OCT systems is that if the skin inflammation becomes too high, it becomes difficult to quantify because OCT can only image to depths of around 1 mm. This limited depth penetration can potentially be improved by using a longer wavelength of laser light. With the project, Stephen Matcher will quantify the improvement in OCT image quality when using 1600 nm light rather than the current 1300 nm light.

If successful, the project holds a strong potential for use in both clinical trials and clinical practice with a highly needed more patient-friendly tool for measuring drug efficacy in skin diseases such as atopic dermatitis.

Investigating the developmental basis for anatomical variations in wound repair and disease susceptibility

Grantee: Tanya Shaw, Senior Lecturer, King's College London

Amount: DKK 2,498,527

Grant category: Research grants in open competition

Year: 2021

Geography: United Kingdom

The aim of this project is to investigate why skin in the facial region heals faster and often with less scarring than the rest of the body but are still prone for other fibrotic diseases like keloid scars. 

Tanya Shaw hypothesizes that this is due to the dermal cells of the face being of a different origin than cells at other sites of the body. Dermal cells of the face stem from so-called neural crest cells and these cells are known for their fast migration and capacity to develop into a multitude of differentiated cells.   

The approach of the project will be to:  

  1. investigate the genetics and epigenetics of keloid scars to determine to what extent they originate from neural crest cells  
  2. compare neural crest cell-derived fibroblasts to fibroblasts from other origins in term of plasticity and cell migration  
  3. manipulate the neural crest cell features in a mouse wound model to investigate if they are critical for wound healing and scarring.   

If the hypothesis can be confirmed, the project holds a strong promise for improvement of wound healing and scarring.   

Identification and biological basis of immunomodulation of skin inflammation by S. epidermidis

Grantee: Peter Arkwright, Senior Lecturer, The University of Manchester

Amount: DKK 4,369,423

Grant category: Research grants in open competition

Year: 2020

Geography: United Kingdom

The ultimate goal of this project is to contribute to the development of new medicines to treat bacterially induced eczema.

The project is a continuation of previous work supported by the LEO Foundation on the impact of bacterial infection, specifically caused by Staphylococcus Aureus (S. Aureus), on eczema. Here, a single factor secreted by S. Aureus was identified as the primary causative agent for eczema development or flare-up. Furthermore, it was also found that the naturally occurring variant, S. Epidermidis, has an inhibitory effect on eczema-induction.

The objective of the present project is to further elaborate on the disease-preventing effect of S. Epidermidis. First, the team will identify any factor(s) secreted by S. Epidermidis that inhibits eczema and then confirm its role by knocking out any relevant gene(s). Finally, the effect of any identified factor(s) on S. Aureus-induced eczema will be studied.

Global Psoriasis Atlas Phase II (GPA 2020-2023)

Grantee: Professor Chris Griffiths, University of Manchester

Amount: DKK 8,000,000

Grant category: Strategic grants

Year: 2020

Geography: United Kingdom

Psoriasis is a significant, life-long and currently incurable skin disease, which, according to the first edition of the Global Psoriasis Atlas (GPA), affects at least 60 million people worldwide.

The need to understand and uncover how psoriasis impacts both the individual and society at large is in demand. The Global Psoriasis Atlas is a long-term project that seeks to become the ‘go-to’ evidence-based resource within the understanding of psoriasis and its effects on people and society all over the World.

GPA Phase II (2020-2023)

The GPA Phase II  is focused on continued research to establish robust data that address existing knowledge gaps within psoriasis on epidemiology, improving diagnosis, comorbid disease and economic impact.

Furthermore, if sufficient and robust data are available, the plan is to perform a pilot implementation study as part of GPA Phase II.

Addressing these key areas and how they differ between countries and regions will support the aim to provide better access to care for people with psoriasis worldwide.

Background

With a mission to ‘ensure that people with psoriasis, wherever they live in the world, have access to the best available care. The grant for the first version of the GPA was granted to Professor Griffiths and the University of Manchester in 2016.

The LEO Foundation has been main funder of the development of the first edition of the GPA through a 3-year grant of DKK 6,370,000 from 2017 – 2020. The GPA project has in its first three years focused on research into the global prevalence and incidence of psoriasis – resulting in the first edition of the GPA website which can be accessed free of charge here: Global Psoriasis Atlas online

The LEO Foundation Award 2019 – Region EMEA

Grantee: Dr. Shoba Amarnath

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2019

Geography: United Kingdom

Shoba Amarnath is a Research Fellow at the Institute of Cellular Medicine at Newcastle University, UK

She receives 100,000 USD for her research in the field of immune tolerance in cutaneous inflammation.

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Mechanisms involved in decreased cutaneous immunity during ageing: reversal by Vitamin D pre-treatment

Grantee: Arne Akbar, Professor of Immunology, University College London

Amount: DKK 4,478,517

Grant category: Research grants in open competition

Year: 2019

Geography: United Kingdom

There is a sterile inflammatory response to needle challenge driven by recruitment of inflammatory monocytes to the skin in old humans. This inflammatory response negatively correlates with cutaneous immunity after injection of varicella zoster virus antigens into the skin. Inhibition of the inflammation associated with the injury response, with a p38-MAPkinase inhibitor, reduced inflammatory monocyte recruitment and significantly enhanced antigen-specific immunity.

The aim of this project is to understand how inflammation and inflammatory monocytes inhibit antigen-specific T cells in the skin of old human volunteers.

The following experimental questions will be addressed: 1) Which cells are responsible for the inflammatory response to needle injury and how does the interaction between the infiltrating monocytes and other inflammatory populations amplify the response? 2) How are the inflammatory monocytes recruited to the site of challenge in the skin? 3) How do the recruited monocytes inhibit antigen-specific immunity in vivo in the old? 4) Using biobanked skin biopsy samples before and after the same older subjects have been treated with Vitamin D, we will determine gene expression signatures of how this treatment enhances cutaneous antigen-specific immunity.

These investigations will identify ways to enhance the immunity of older humans to vaccination and also infection and malignancy.

Establishing the keratinocyte stem cell basis for skin field cancerisation and squamous cell carcinoma

Grantee: Girish Patel, Honorary Senior Lecturer, Cardiff University

Amount: DKK 3,935,737

Grant category: Research grants in open competition

Year: 2019

Geography: United Kingdom

Epithelial tissues, the environmental barriers of our bodies, are constantly exposed to cancer causing agents. As such carcinoma, the cancer of epithelial tissues, are the most common form of cancer accounting for 85% of all cancers and 78% of all cancer associated deaths.

Many carcinomas arise from a pre-cancerous transformation, known as intraepithelial neoplasia or field cancerisation (FC), within which multiple carcinoma can develop.

By studying skin FC in a mouse model of human papillomavirus 8 infection (K14-HPV8-CER), we have uncovered specific expansion of only the Lrig1 hair follicle junctional zone keratinocyte stem cells (HFJZKSC) driven by ΔNp63 expression, which is the basis for skin FC 1-3.

These findings raised two important fundamental questions:

  1. How does HPV8 induce Lrig1 KSC expansion? The background for this proposal and ongoing work (Leo Foundation grant 2017, LF17070).
  2. Are Lrig1 derived cells responsible for squamous cell carcinoma (SCC)? The basis for this Leo grant proposal.

The current Leo Foundation grant allowed us to identify E6 as the HPV8 protein responsible for Lrig1 KSC expansion through activation of the STAT3 intracellular signalling pathway.

Therefore, we are now positioned for a follow-on grant to determine whether Lrig1 derived cells are responsible for FC associated SCC. Herein we aim to:

1) confirm that Lrig1 HFJZKSC proliferation is responsible KSC expansion into the infundibulum and adjoining interfollicular epidermis

2) test the hypothesis that Lrig1 HFJZKSC progeny give rise to papilloma and SCC

3) determine whether STAT3 mediate HFJZKSC expansion occurs in human skin FC.

Implementation of novel 3-bounce 2-pass ATR FTIR spectroscopy into the Skin Testing for Atopic dermatitis (STAR) study

Grantee: Dr Simon G. Danby, Independent Research Fellow, The University of Sheffield Medical School

Amount: DKK 390,506

Grant category: Research grants in open competition

Year: 2018

Geography: United Kingdom

With this grant, the group led by Simon G. Danby seeks a potentially important technological addition to the ongoing A longitudinal investigation of skin barrier development from birth and the validation of early predictors of Atopic dermatitis (AD) risk: the skin testing for atopic dermatitis risk (STAR) trial (see Grants 2017).

This addition may prove valuable to the group’s envisioned paradigm shift – from management of established AD to primary prevention of the condition.

More specifically, the group will include enhanced ATR-FTIR spectroscopy to quantify biomarkers of skin barrier condition and AD severity in newborns. While existing spectroscopy works in adults and children, its sensitivity has been proven unsatisfactory when measuring newborns.

Working with the equipment manufacturer, the group has developed a solution that increases sensitivity 6-fold. This increase can help better prediction of the risk of AD in the newborn and thus enable targeted emollient intervention right from birth – potentially leading to a reduction of the incidence of the condition as increasing evidence suggests that topical emollient therapy can prevent the initial onset of AD by 50%.

AD is a very common chronic inflammatory skin condition affecting around 20% of children worldwide. The disease often heralds development of allergic diseases such as food allergy, asthma, and allergic rhinitis.

Project Group

Prof. Michael J. Cork and Mr J. Chittock, The University of Sheffield, United Kingdom

Dame Prof. Tina Lavender and Dr Alison Cooke, The University of Manchester, United Kingdom

Elucidating the stem cell basis for skin field cancerisation

Grantee: Dr Girish Patel, Senior Lecturer at the European Cancer Stem Cell Research Institute, Cardiff University, Wales

Amount: DKK 1,704,758

Grant category: Research grants in open competition

Year: 2017

Geography: United Kingdom

Gish Patel from Cardiff University in Wales leads an international collaboration of experts in a project that investigates the signalling pathways responsible for malignant transformation of skin epithelial cells. The hope is to identify novel therapeutic targets for future drug discovery and development.

Epithelia are continually exposed to environmental carcinogens and therefore, cancers of epithelial tissues called carcinoma, account for 85% of all cancers and 78% of all cancer-associated mortality.

Many carcinomas arise from pre-malignant transformation as intraepithelial neoplasia, also referred to as field cancerisation (FC). FC can give rise to multiple primary cancers and is a feature of malignancies involving many organs, including the skin.

The team hypothesises that the mechanism in skin FC arises from dysregulation of a particular signalling pathway. This is based on results from a murine model on Epidermodysplasia Verruciformis, where the team uncovered a novel keratinocyte stem cell (KSC) basis for the FC.

This is potentially relevant to FC in other tissues and the team targets utilisation of an innovative multiple-strategy approach to determine a drug-targetable signalling pathway involved in malignant transformation and expansion of this novel KSC population.

The LEO Foundation Award 2016 – Gold Award

Grantee: Dr. Amaya Virós

Amount: DKK 1,000,000

Grant category: LEO Foundation Awards

Year: 2016

Geography: United Kingdom

Presented to Dr. Virós who has made important contributions to the area of skin research by describing mechanisms behind the development of squamous cell carcinoma and melanoma. She has published in top-ranking scientific journals and received a number of prestigious awards, including a recent Wellcome Trust Intermediate Clinician Scientist Fellowship to set up her laboratory at the Cancer Research UK Manchester Institute in the newly-built Manchester Cancer Research Centre, UK, which is based at The University of Manchester.

Dr. Virós will focus her future research on the under-researched area of skin cancer and ageing. Ageing skin appears to have unique properties and patterns of tumour development that may explain the surprising increase in aggressive primary melanoma and mortality from this disease. Her aim is to identify the factors in elderly people that make them more prone to developing melanoma and less likely to survive once they develop the disease.