GLP-1R signaling in T cells in relation to psoriasis

Grantee: Carsten Geisler, Professor and Head of Department, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen

Amount: DKK 2,000,000

Grant category: Research grants in open competition

Year: 2017

Geography: Denmark

Recent studies of patients with psoriasis and type 2-diabetes have shown intriguing results: administration of glucagon-like peptide 1 (GLP-1) analogues was found to improve the severity of psoriasis. In another study, while not finding a significant beneficial effect of a GLP-1 analogue on disease score as compared to placebo, patients did report a significant decrease in their disease score as compared to baseline.

This has led a Denmark-based group to team up for further investigation of the effect of GLP-1 analogues on psoriasis, based on, among others, an assumption of a direct effect of GLP-1 analogues on the immune system – with the intention of clarifying if there may be a route to new treatment options for psoriatic patients.

More specifically, the team will investigate if the potential immunoregulatory effect of GLP-1R signalling on T cells in psoriatic plaques could be responsible for the patient-experienced alleviation of psoriasis. The team furthermore hypothesizes that vitamin D may play an important role in GLP-1R signaling and is important for alleviation of psoriasis as Vitamin D upregulates GLP-1R on T cells and low serum levels of vitamin D have been reported in psoriatic patients.

The majority of the experiments will be performed by Anna Kathrine Obelitz Rode under supervision of Martin Kongsbak-Wismann and Carsten Geisler, Department of Immunology and Microbiology, University of Copenhagen. Lone Skov, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen will be co-supervisor on the project. The project will be performed in close collaboration with Charlotte Menné Bonefeld, Department of Immunology and Microbiology, University of Copenhagen.

The clinical studies in humans will be performed at the Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen in collaboration with Lone Skov.

The pro-autophagic tumor suppressor AMBRA1 as a novel therapeutic target for melanoma

Grantee: Professor Francesco Cecconi, Head of the Cell Stress and Survival Unit (CSS), Danish Cancer Society Research Center (DCRC), Copenhagen

Amount: DKK 3,820,000

Grant category: Research grants in open competition

Year: 2017

Geography: Denmark

The LEO Foundation has supported this project in appreciation of the fact that malignant melanoma has the highest death toll among skin cancer.

If and when melanoma is not diagnosed and treated early, the cancer may develop and spread to other parts of the body, where it becomes harder to treat and potentially fatal. Therefore, work to find new therapeutic targets for this particular aggressive cancer type is of extreme importance.

Professor Cecconi and his team have extensive and comprehensive expertise on the molecular ‘switch’ AMBRA1, believed to play a significant role in the body’s own defense against diseases such as cancer.

As an example, professor Cecconi was the first to identify the AMBRA1 gene and has been unraveling its multiple functions over the last 10 years. In particular, he has already demonstrated AMBRA1 playing a role as tumor suppressor in vivo, and preliminary data indicates the gene’s supposed role as a therapeutic target in cancer. Very intriguingly, most AMBRA1 mutations were found in melanoma patients.

The LEO Foundation finds this project to be innovative and commends its multidisciplinary approach, putting together different fields of research ranging from cell biology, mouse genetics, biophysics, computational biology and CRISPR/Cas9 technology.

Prof. Cecconi is member of the European Consortium Mel-Plex (Horizon 2020 Marie Curie Action), which includes several international researchers with the common aim of tackling melanoma – and these existing collaborations with melanoma experts will be of great importance in order to accomplish the project.

Instantaneous monitoring of allergic reactions in the skin

Grantee: Stephan Sylvest Keller, Associate Professor, DTU Nanotech

Amount: DKK 600,000

Grant category: Research grants in open competition

Year: 2017

Geography: Denmark

Allergy is one of the world’s most common chronic conditions. It is caused by immunoreaction of the human body towards in principle otherwise harmless allergens, and the current method for allergy screening and monitoring is the skin prick test (SPT) where different allergens are introduced into the tested person’s skin.

This widely used method, however, is non-quantitative, relatively lengthy and patients might experience unpleasant reactions. Furthermore, clinical evaluation of the SPT requires physical assessment of visible changes of the skin due to local inflammation by an experienced health care professional.

In the supported PhD project, which involves collaboration between DTU Nanotech, the Allergy Clinic at Gentofte Hospital in Denmark, Malmö University in Sweden and the University of British Columbia in Canada, an allergy test based on a micropatch will be developed which may be both more efficient and accurate as well as less cumbersome.

The micropatch will introduce allergens to the skin with carbon micro needles and allow for instantaneous and quantitative monitoring of allergic reactions in the skin through in vivo electrochemical sensing of the histamine released from activated mast cells in the interstitial fluid.

If successful, the new micropatch-based test will provide for less unpleasant allergy tests, in particular relevant with children suffering from atopic dermatitis. Further, a successful micropatch test will be a valuable and effective mean to identify potential immunoreactions towards newly developed topical dermatological drugs.

The project is supported by the LEO Foundation, the Copenhagen Center for Health Technology – CACHET (www.cachet.dk) and DTU Nanotech.

Investigation of atopic dermatitis in Greenland; distinct genotypes, phenotypes, and immunotypes

Grantee: Jacob Pontoppidan Thyssen, Consultant, PhD, DMSc, Assistant Professor, Department of Dermatology and Allergy, Herlev and Gentofte Hospital

Amount: DKK 5,078,619

Grant category: Research grants in open competition

Year: 2017

Geography: Denmark

The LEO Foundation supports this study aimed at improving diagnostic accuracy and treatment of Atopic dermatitis (AD) in Greenland, and to add to the general knowledge of AD.

The project’s hypothesis is that Inuit children with AD residing in Greenland display a population-specific prevalence, set of risk factors, phenotype, genotype, immunotype, and bacterial load. As part of showing this, it is intended to clarify potential Inuit-specific loss-of-function mutations in filaggrin gene (FLG) addressing the latitude dependent gradient in FLG mutation prevalence and its potential role in providing an evolutionary advantage.

In general, the settings in Greenland differ on many parameters from a conventional western society: The AD study population is expected to be different due to variation in living conditions, diet, climate, and genetic admixture. This is of particular importance to better examine and understand AD etiology and related risk factors and may hopefully provide a break-through in AD research.

In the project, the team will establish a large children cohort in Greenland to estimate prevalence, genotype, phenotype, immunotype, and risk factors for AD. By examining Inuit children with and without AD, compared with Danish children with AD, along with a cohort comparison from collaborating partners, the team will be able to examine whether phenotypic traits correlate with genotype, immunotype, ethnicity, or environmental factors, including gut and skin microbiomes.

The study offers an exclusive opportunity to examine AD in a homogenous small population in a secluded environment, and is foreseen to contribute to increased understanding of AD as an overall term, hereby its phenotype, genotype, immunotype, and specific risk factors. Both to understand better the pathogenesis of AD, and to improve and implement diagnostic tools for Greenlandic patients with AD.

Development of elastin-based biomaterials for wound healing

Grantee: Assistant Professor Andrea Heinz, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen

Amount: DKK 1,472,000

Grant category: Research grants in open competition

Year: 2017

Geography: Denmark

Wound healing is a complex biological process involving interaction of different types of cells, mediators, and components of the extracellular matrix.

In particular, re-epithelialization, closure of the wound by the epithelial cells, is a crucial step as it re-establishes skin continuity. The process, however, may be impaired in various pathological conditions such as diabetes, leading to the development of acute or chronic non-healing wounds.

This project, involving participants from Denmark, France, and Germany, aims to develop wound dressings based on novel polymer- and protein-based biomaterials capable of delivery of bioactive molecules. The basis will be elastin, an extracellular matrix protein with unique properties such as elasticity and biocompatibility.

In order to form the 3D scaffolds needed for wound dressings, state-of-the-art electrospinning will be utilized and hydrogels will be prepared by in vitro cross-linking of elastin-based peptides. The conditions of preparation will be tuned to produce a biomaterial of desired mechanical properties, which will then be characterized physio-chemically using a range of analytical techniques.

Addition of bioactive peptides and growth factors will allow for stimulation of wound healing. The materials will be tested in vitro using human fibroblast cell cultures and in vivo using animal wound models.

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.

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.