Grant category: Research Grants in open competition

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.

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.

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.

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.

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.

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.

Grant category: Research Grants in open competition

Year: 2016

Geography: Denmark, Germany, Netherlands

The study is foreseen to increase the understanding of the skin barrier and immune system in atopic dermatitis.

Through international collaboration with scientists who perform state of the art and pioneering analyses on skin samples as well as national collaboration with immunologists and radiologists, the team will seek to evaluate non-invasive and easily collectable biomarkers that can predict the risk for atopic dermatitis.

The study has the potential to provide insight in atopic dermatitis pathogenesis and the value of promising pre-atopic dermatitis biomarkers that indicate both inflammation and skin barrier barriers dysfunction. This could be used to develop an algorithm that can better predict the onset of atopic dermatitis.

The team’s work may thus substantially increase the understanding of skin biology in neonates, both normal and diseased. The study will also provide a basis for not only future large-scale observational studies, but also randomised controlled studies evaluating the efficacy of preventive skin barrier restoration or anti-inflammatory treatment in selected groups, potentially reducing the incidence and complications of the most common skin disease in childhood.

Grant category: Research Grants in open competition

Year: 2016

Geography: Australia, Singapore

This research project, led by Dr Philip Tong from the University of Sydney, has the potential to represent a technological advancement in the field of human skin immunological research. By use of 3D histological reconstruction and computational image analysis, the aim is to develop the world’s first Human Skin Immune Atlas of dermal immune populations in normal and diseased skin.

The members of the team assembled for this project are already established experts in the fields of skin immunology, microscopy, inflammation and computational analysis, and the project will have an international platform with sites across Asia and Oceania.

The skin is a complex organ, wherein topographical and micro-compartmental specialisation of the immune system has been demonstrated. The general spatial understanding of the skin immune system has been advanced through the use of transgenic laboratory animals with live imaging tools. These, however, have yet to be validated in humans. The work realised in this project may provide fundamental insights into the human skin immune system.

Moreover, the data generated may have wide reaching implications for the development of better in vitro skin substitutes, validation of in vivo microscopic skin imaging tools for human use and improved quantification of skin inflammation in clinical trial settings.

Grant category: Research Grants in open competition

Year: 2016

Geography: USA

Atopic dermatitis (AD), or atopic eczema, is the world’s most common inflammatory skin disorder. Its prevalence has increased during the past few decades and can now be found to be more than 20% in children and 10% in adults.

For children, there is an unmet need for improved therapy for moderate to severe AD and it is likely that therapeutics with proven safety and efficacy in adults will move towards to trials in children. There are, however, when gauging the pathogenesis and characteristic biomarkers related to AD, significant differences between children and adults.

Dr. Guttmann’s study purports to shed light on these differences to enlarge the understanding of biomarkers and to clarify when children transition to the adult biomarker pattern that predicts responses. Correlating the validity of biomarkers in adults with AD vs. different age groups of children and adolescents with AD (including 5-12 and 12-17 years olds) is a critical step before engaging in large clinical trials.

Given the challenge in obtaining biopsies from children during clinical trials, defining a set of biomarkers in blood will prove extremely valuable in these large patient populations. More specifically, the study will address the following questions:

• What are the cutaneous biomarkers in AD in children and adolescents of different age groups and how do these compare with disease activity, epidermal barrier function, and known biomarkers in both infancy/early childhood and adult AD skin?
• Are there useful biomarkers in the blood of children and adolescents with AD that compare well with skin immune and barrier biomarkers, and could these enable a less invasive means to follow biomarker changes and direct skin therapy than skin biopsies?
• At what age do children acquire an “adult” AD phenotype?

Grant category: Research Grants in open competition

Year: 2016

Geography: United Kingdom

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin conditions and prevalence of the disease seems to grow. Early onset of AD is often followed by development of other allergic conditions such as food allergies, asthma and allergic rhinitis – all together the most chronic diseases of childhood and a major financial burden to health services.

Evidence suggests that a skin barrier defect is the primary event in development of AD.

With this research project, a longitudinal neonate/infant cohort study, the team led by Dr Simon G. Danby seeks to investigate the development of the skin barrier from birth, before the development of AD, to 12 months of age, when the majority of AD cases have developed. The team has extensive experience in the characterisation of the skin barrier in AD patients and in conducting clinical trials in neonates.

In the study, the team will compare three technologies for the quantification of established biomarkers attributed to skin barrier function and AD severity, for their accuracy and feasibility at predicting onset of AD by 12 months of age.

In addition, the team’s multi-analytical approach may provide new insights into skin barrier development in neonates and the identification of tools that could help determine who do and do not go onto develop AD. The study thus has the potential to help drive forth a new generation of patient solutions specifically designed for neonates at risk of developing AD.