Genetic mechanisms of acne vulgaris

Grantee: Michael Simpson, Professor of Genetics, King's College London

Amount: DKK 2,870,799

Grant category: Research grants in open competition

Year: 2022

Geography: United Kingdom

The aim of Michael Simpson’s project is to identify potential cellular or molecular targets for acne treatment, based on analysis of genetic variation found in a large pool of acne patients.

Acne vulgaris is a very common skin disease which is characterized by clogging and inflammation of the pilosebaceous unit, which consists of a sweat gland and a hair follicle including the hair itself. While various potential causes leading to the disease have been investigated over the years, the underlying disease mechanisms have not yet been sufficiently elucidated. One common approach to learning more about cellular and molecular causes for development of disease in some people is to investigate changes in the genes that influence the behavior and communication paths of cells – the signaling cascades known to be involved in the disease. Michael and his team have previously identified several areas (loci) in the human genome which are associated with acne.

They now want to study these areas in further detail to better understand the causal molecular and cellular events that lead to acne and hopefully identify targets for treatment. They will use a three-step approach. Firstly, by identifying the genetic variants linked to the disease by analyzing genetic data from more than 60,000 individuals with acne. Secondly, they will cross-link these variations to create a map of the signaling pathways and associated cells responsible. Finally, based on this mapping, they expect to be able to identify targets for future treatments of the disease. If successful, the results may provide the first steps towards a better and more targeted treatment for this very common and socially stigmatizing skin disease.

A single-cell dissection of the mechanisms underlying the ocular adverse effects of dupilumab in atopic dermatitis

Grantee: Francesca Capon, Associate Professor, King's College London

Amount: DKK 2,053,475

Grant category: Research grants in open competition

Year: 2022

Geography: United Kingdom

This project, led by Francesca Capon, investigates the molecular and cellular mechanisms of dupilumab-associated conjunctivitis (inflammation of the eye), a comorbidity seen in one in three AD patients treated with the drug.

These mechanisms are poorly understood, and Francesca’s team wants to elucidate them by comparing immune profiles in blood samples from affected and non-affected patients. In addition, they will identify inflammatory molecules released by cultured immune cells treated with dupilumab to further understand the key signaling pathways.

The findings will enhance the understanding of dupilumab-induced conjunctivitis and eventually help improve treatment of patients with this condition.

Understanding the pathogenesis of steatocystoma multiplex

Grantee: Edel O'Toole, Professor, Queen Mary University of London

Amount: DKK 2,846,085

Grant category: Research grants in open competition

Year: 2021

Geography: United Kingdom

This project, led by Edel O’Toole, aims to give new insights into the rare genetic skin disease, steatocystoma multiplex (SM) that may contribute to the development of a new treatment for affected individuals.

SM is a debilitating and embarrassing disorder, which presents as multiple smooth, yellow skin lumps or cysts distributed on the arms, trunk, neck, and underarm area. The lesions usually appear in the teenage years and for the severely affected patients with 100s to 1000s of cysts, these are a major burden causing disability and pain with frequent inflammation often mimicking infection.

The most common genetic defect is found in the gene coding for Keratin 17, a protein expressed in nails, hair follicles, skin on the palms and soles, and in sebaceous glands. The cysts in SM are believed to arise from the lining of these glands. The team will use single cell RNA sequencing and look at gene expression in individual cells lining the cyst and from the surrounding tissue, to understand the genetic differences.  In parallel, the O’Toole group will engineer cells from the sebaceous gland with and without the defect in the Keratin 17 gene. These cells will be used to form 3D skin models and cysts that mimic SM. Finally, drugs that target pathways of interest identified from the RNA sequencing will be used to ‘treat’ the 3D model, thereby adding to the many insights around SM expected from this project.

New diagnostic tool for scleroderma based on the detection of non-coding RNA biomarkers from skin interstitial fluid

Grantee: Claire Higgins, Senior Lecturer, Imperial College London

Amount: DKK 3,436,300

Grant category: Research grants in open competition

Year: 2021

Geography: United Kingdom

Claire Higgins’ project aims to develop an early-stage diagnostic tool for scleroderma, a disease caused by an overproduction of collagen in both the skin and connective tissues, leading to a scarring of the skin and internal organs.

Among the early symptoms of scleroderma are poor blood circulation in fingers and toes, and an increased sensitivity to cold, which in many aspects is comparable to the much more common Raynaud’s phenomenon, and hence, scleroderma is often undiagnosed.

Utilizing the fact that certain molecules change expression level during disease (‘biomarker’ molecules), Claire Higgins aims to identify scleroderma-specific biomarkers in the liquid between individual skin cells, i.e., in the skin interstitial fluid. The identified biomarkers will be used to develop a non-invasive and painless test for general practitioners (GPs), enabling fast diagnosis – within minutes – and thereby differentiation between patients suffering from scleroderma and Raynaud’s phenomenon. Thus, patients will be able to get the most relevant intervention as early as possible. The actual diagnostic test will be developed along with the biomarker identification.

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: 2020

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.

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