p14-ARF in familiar melanoma: a promising target that acts as a melanocyte guardian
Grantee: Elena Papaleo, Junior Group Leader, Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen
Amount: DKK 1,300,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
Melanoma is one of the most aggressive skin cancers and its incidence in Denmark has increased over the last decade, becoming the most frequent type of cancer in young women. Despite recent discoveries on melanoma mechanisms, the prognosis for the patient is still poor and extensive research efforts are needed to clarify the molecular mechanisms involved and identify new therapeutic targets.
The outcome of this project has the potential to join these efforts by advancing the comprehension of metabolic reprogramming which forms the basis for aggressiveness and resistance to treatments in familial melanoma.
The most common mutations in familial melanoma are found in genes encoding the proteins INK4A and p14-ARF (ARF), and the basis for the project is the newly discovered function of ARF to act as guardian in human melanocytes by maintaining low levels of superoxide in conditions of mitochondrial dysfunction, protecting the melanocytes from reactive oxygen species.
The protective mechanisms mediated by ARF rely on its physical interaction with BCL-xL, a trans-membrane molecule, and this interaction could be disrupted by germline mutations of ARF. The understanding of the interaction mode and how mutations interfere with them is a fundamental step to target the BCL-xL/ARF complex for therapeutic purposes.
Carried out in a cross-disciplinary environment at the Danish Cancer Society Research Center, the project brings together experts in cellular cancer biology, structural biology, and bioinformatics. The team has access to many supercomputing facilities to speed up the data acquisition of the envisioned time-consuming simulations.
Regulation of IL-22 secretion by vitamin D in relation to Atopic Dermatitis
Grantee: Carsten Geisler, Professor and Head of Department, Department of Immunology and Microbiology, University of Copenhagen
Amount: DKK 2,779,900
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
Atopic dermatitis (AD) is a common skin disorder affecting up to 25% of children and 3% of adults. Currently, no good treatment options exist and AD has a large impact on quality of life.
The skin of AD patients’ is characterized by inflammation caused by infiltration of both dendritic cells (DCs) and T cells leading to among other highly itching plaques. Furthermore, AD lesions are prone to infections due to a decreased barrier function of the skin.
A newly described T cell subset, Th22 cells, is suggested as a main driver of AD with an increased infiltration of both Th22 and Tc22 cells correlating with disease severity.
Treatment with narrow-band ultraviolet B radiation (NB-UVB) has proven effective in reducing the disease-scoring index of AD patients. This is accompanied by a suppression of the Th2/Th22 axis and there are ongoing clinical trials with blocking antibodies against IL-22 for AD treatment.
UVB radiation of skin is known to initiate the production of vitamin D with its potent immunomodulatory properties, and it shows that activation of human CD4+ T cells leads to a secretion of IL-21 and IL-22 – a secretion that therefore can be inhibited by vitamin D.
This project will investigate the effects of vitamin D in a physiologically relevant in vitro differentiation system of CD4+ T cells towards the Th22 lineage, targeting a better understanding of the interplay between the developments of Th22 cells in relation to AD.
Furthermore, the project will potentially provide a basis for the understanding of the molecular and cellular events in AD, and the possible symptom alleviation of patients following topical treatment with vitamin D analogues.
Replicating peeling skin diseases in a living skin model
Grantee: Professor Peter R Hull, PhD (Med) FRCPC. Head, Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, Nova Scotia
Amount: DKK 2,180,881
Grant category: Research Grants in open competition
Year: 2017
Geography: Canada
A number of chronic skin conditions have peeling of the skin as the dominant expression; akin to skin peeling following severe sunburns. In the chronic conditions, peeling is cyclical or continuous, often affecting hands, feet, or the body. Today, there is no effective treatment for these conditions, leaving patients subjected to trial and error with a variety of non-effective and often also expensive therapies.
A number of abnormal gene variants have been found to disrupt the normal maturation of the skin. Using a gene manipulation tool known as CRISPR, the team led by Dr Hull will build understanding of the role of four known genes causing skin peeling syndromes. This will be done by replicating the diseases in cell cultures grown into full thickness skin and studying the cellular and biochemical changes caused by the induced gene modifications.
Of particular interest is cathepsin B, an enzyme that has been found to play an important role in peeling associated with the skin disorder, keratolytic winter erythema.
The team’s hypothesis is that there is an important and dynamic interplay and balance between a number of enzymes in the outer layers of the skin and that if this balance favours the activity of cathepsin B, peeling results.
If this is shown, it may be clinically very relevant as there are a number of known compounds that inhibits cathepsin B and which then could be used to treat patients with chronic peeling as a consequence of their skin disorder.
The function and therapeutic potential of miR-146 family in the suppression of Type-2-cell-promoting environment in atopic dermatitis
Grantee: Ana Rebane, PhD, Head of the RNA Biology Research Group, Institute of Biomedicine and translational Medicine, University of Tartu
Amount: DKK 1,650,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Estonia
Atopic dermatitis (AD) develops because of skin barrier abnormalities leading to activation of keratinocytes (KCs) and development of Type-2-cell- mediated chronic skin inflammation.
While the initial molecular events leading to induction of Type-2-cell-promoting cytokines are not well defined, it has been suggested that activation of the NF-kB pathway in response to environmental and/or intrinsic factors in KCs may be at play.
Concurrently, microRNAs – in particular miR-146a and miR-146b (miR-146a/b) – which are post-transcriptional gene expression regulators modulating various biological processes, have been shown to have an anti-inflammatory function in KCs and in the chronic phase of skin inflammation in AD.
In this project, Dr Rebane hypothesizes that miR-146a/b might inhibit AD-promoting events in the skin as these microRNAs act by targeting multiple factors in the NF-κB pathway.
Dr Rebane aims to study this relation using tissue culture and murine models, and assess the therapeutic potential in the regulation of Type-2-cell-promoting cytokines in the development of AD. In addition, it is planned to describe the expression of miR-146a/b isoforms and novel AD associated miRNAs in the skin of AD patients with the aim of detection of novel therapeutic targets.
The spatial composition and distribution of the cutaneous microbiota in atopic dermatitis and healthy skin
Grantee: Professor Thomas Bjarnsholt DMSc, PhD, Costerton Biofilm Center, Department of Immunology and Microbiology, and Department of Clinical Microbiology, University of Copenhagen
Amount: DKK 2,857,565
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
In this study, Dr Bjarnsholt looks at skin microbiota and expects to illuminate consistencies and differences between atopic dermatitis and healthy skin. He will do so with focus on the cutaneous microbial composition and spatial distribution in the different layers in AD relative to healthy skin.
The skin microbiota is recognised to significantly impact human health but remains incompletely characterised in the pathogenesis of common cutaneous conditions such as AD. Understanding the three-dimensional distribution of bacteria within the skin may provide relevant insights regarding transition from healthy to diseased skin.
This study will compare the distribution and composition of the commensal, skin microbiota in dry, moist and sebaceous environments as they relate to early onset in AD patients relative to healthy volunteers.
Tape strips and sub-divided skin biopsies will be sampled and analysed by three informative, supplementary methods, i.e. cultivation, Confocal Laser Scanning Microscopy (CLSM) and Next Generation Sequencing (NGS).
This is foreseen to show how the microbiota changes in immediately adjacent regions of tissue among diseased and healthy individuals. In addition, generation of high-resolution, 3D images by confocal microscopy will allow visualisation and confirmation of the molecular and culture results.
The LEO Foundation Award 2016 – Silver Award
Grantee: Dr. Thomas Wiesner
Amount: DKK 500,000
Grant category: LEO Foundation Awards
Year: 2016
Geography: Austria
Presented to Dr. Thomas Wiesner. Dr. Wiesner is breaking new ground to find new mechanism-based cancer therapies. Following medical school, Dr. Wiesner wrote his thesis on the genomic aberrations of cutaneous lymphoma and completed his residency in dermatology at the Medical University of Graz in Austria. Dr. Wiesner spent five years conducting basic and translational research using cutting-edge techniques within high-throughput sequencing techniques in particular. His work within skin cancer research resulted in key discoveries, in particular concerning the genomic landscape of skin tumours.
Based on his experience as a physician-scientist and his access to high-quality clinical samples, Dr. Wiesner plans to combine high-throughput sequencing technologies, computational approaches and functional assays in order to define the relevant genomic and epigenomic aberrations in skin cancer and pave the way for new mechanism-based cancer therapies.
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.
The LEO Foundation Award 2016 – Silver Award to young scientist in Japan
Grantee: Dr. Yu Sawada, research fellow, Department of Dermatology, Kyoto University and assistant professor, University of Environmental and Medical Health, Kitakyushu
Amount: DKK 250,000
Grant category: LEO Foundation Awards
Year: 2016
Geography: Japan
The LEO Foundation has offered the LEO Foundation Silver Award 2016 to Yu Sawada for his pioneering dermatological research. The award has been bestowed in collaboration with the Japanese Society for Investigative Dermatology (JSID).
The award ceremony took place in Sendai, Japan, at the 41st annual conference of JSID on 11 December 2016.
Dr. Yu Sawada currently holds the position as a research fellow at the Department of Dermatology in Kyoto University and assistant professor at the University of Environmental and Medical Health in Kitakyushu. Dr. Sawada’s research focuses on establishing and implementing a new therapeutic paradigm for the improvement of inflammatory skin diseases through medical treatment in combination with specific lifestyle alterations such as diet, sleep and physical exercise.
The LEO Foundation Award 2016 – Gold Award to young scientist in Japan
Grantee: Dr. Ayumi Yoshizaki, lecturer and independent researcher, Department of Dermatology, Graduate School of Medicine, The University of Tokyo
Amount: DKK 500,000
Grant category: LEO Foundation Awards
Year: 2016
Geography: Japan
The LEO Foundation has offered the LEO Foundation Gold Award 2016 to Ayumi Yoshizaki for his pioneering dermatological research. The award has been bestowed in collaboration the Japanese Society for Investigative Dermatology (JSID).
The award ceremony took place in Sendai, Japan, at the 41st annual conference of JSID on 11 December 2016.
Dr. Ayumi Yoshizaki is a lecturer and an independent researcher in the field of dermatological autoimmune diseases based at Department of Dermatology, Graduate School of Medicine, The University of Tokyo. Dr. Yoshizaki has his own research group, an impressive list of publications and is well acknowledged by the Japanese dermatological and scientific communities. His future research is focused on autoimmune diseases related to the skin, particularly systemic sclerosis (SSc). His lab uses highly innovative techniques to explore the role of auto-reactive B cells in SSc at the single cell level. He is a rising star that very well could establish himself as a leader in his field globally.
Influence of microbes on development of skin diseases
Grantee: Anders Johannes Hansen, PhD, Associate Professor, University of Copenhagen, Denmark, Robert Gniadecki, MD, Professor, Dermatology Department, Bispebjerg Hospital, Copenhagen, Denmark, Kim Holmstrøm, R&D Manager, Department of Biomedical Technology, Bioneer A/S, and Nicola Segata, PhD, Assistant Professor and Principal Investigator, Computational Metagenomics, CIBIO, University of Trento, Italy
Amount: DKK 5,035,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, Italy
By combining new data from the human skin microbiome with existing knowledge of pathophysiology and clinical phenotypes of Atopic Dermatitis, AD, Actinic Keratosis, AK and non-melanoma skin cancer, the team will seek to establish a novel understanding of these diseases.
Recent microbiome analyses have revealed that mammalian body surfaces are colonized by vast numbers of bacterial communities, which motivates the exploration of the role of the microbiota in normal and diseased skin. There are indications that the skin microbiome plays a key role in both inflammatory skin disease and non-melanoma skin cancer.
The vision for the team’s research endeavours is to explore the microbiome for the identification of new targets for treatment, and for the development of improved treatment modalities for patients with AD, AK and non-melanoma skin cancer.
The team’s explorations will potentially also lead to the development of better and more specific and sensitive diagnostic and prognostic methods for monitoring skin disease.
The Danish-Italian team will work from a unique microbiome discovery platform established at the University of Copenhagen (UCPH) within the GenomeDenmark Cancer & Pathogen project. The platform utilizes procedures enriching various types of microbes combined with state of the art DNA and RNA sequencing and bioinformatics data analysis.