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.
Skin barrier dysfunction and thymus size during the first year of life as predictors for atopic dermatitis
Grantee: Jacob P. Thyssen MD PhD DmSci, Trine Danvad Nilausen MD, Lone Skov MD PhD DmSci, Dep. Dermatology and Allergology, Herlev-Gentofte Hospital, Hellerup, Denmark, Caroline Ewertsen MD PhD, Department of Radiology, Rigshospitalet, Copenhagen, Denmark, Charlotte Bonefeld PhD, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Pal Szecsi MD DmSci, Department of Clinical Biochemistry, Herlev-Gentofte Hospital, Hellerup , Denmark, Sanja Kezic PhD, Coronel Institute, AMC, University of Amsterdam, The Netherlands, and Christoph Riethmüller PhD, nAnostic Institute, Centre for Nanotechnology, University of Münster, Germany
Amount: DKK 2,558,500
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.
Developing deep understanding of atopic dermatitis
Grantee: Joel Dudley, PhD, Director of Biomedical informatics, Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA, and Jeanne Duus Johansen, MD, DMSc, Director National Allergy Research Centre, Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Denmark
Amount: DKK 11,100,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, USA
Atopic dermatitis (AD) and hand dermatitis are heterogeneous disease entities and there has yet to be developed a good understanding of their many different clinical aspects. Thus it remains extremely challenging to provide patients with better treatment outcomes and prognosis.
A newly formed team of scientists at Gentofte Hospital in Copenhagen and Mount Sinai in New York has set out to change this.
“Next generation sequencing and advanced bioinformatics technologies give us powerful new opportunities to explore and understand the molecular pathophysiology of atopic dermatitis and hand dermatitis,” said Dr. Joel Dudley, Director of Biomedical informatics at Icahn School of Medicine, Mount Sinai in New York.
“It is a study that has not previously been performed, and we expect to make a breakthrough in the understanding, classification and treatment of these skin diseases. We hope to improve our knowledge and understanding of the molecular basis of atopic dermatitis and hand dermatitis and their relation to clinical features. Consequently, we also hope to pave the way for improved opportunities for managing and preventing disease,” said Dr. Jeanne Duus Johansen from the Department of Dermato-Allergology at Gentofte Hospital.
She and Joel Dudley will lead a trans-Atlantic team of researchers working with high-throughput, genome-wide profiling of multiple of the ‘–omics’ modalities, including genome, transcriptome, epigenome, and microbiome.
The goal is to develop a deeper understanding of how the molecular manifestation of the heterogeneous diseases correlates with clinical variables such as onset of disease and treatment outcomes. The technologies employed by the team can provide comprehensive molecular profiles that can enhance the understanding of the system-wide mechanics and properties of complex biological systems.
Dudley’s team will integrate the ‘-omics’ data sets to clarify the complex biological mechanisms underlying disease. They will do so by connecting molecular profiles with clinical data to identify molecular surrogates of drivers of important clinical features of disease.
The study will build on previous efforts to assemble and characterise a Danish cohort of individuals affected by AD in adulthood and/or hand dermatitis. The proposed study will add important new dimensions of molecular information that will enable new insights into molecular mechanisms and features of disease. Furthermore, the team sees that an incorporation of molecular measures, namely microbiome and epigenome, may offer insight into environmental correlates or determinants of disease.
Finally, the team foresees that the data and results generated may serve as an important new asset to the AD and dermatology research communities.
“We believe that the data and results generated by our study will enable new research directions and insights into AD and dermatological disease. Furthermore, we believe that such future insights would be enabled by the unique availability of the proposed comprehensive multi-omics data set integrated with comprehensive clinical data and assessment of a large patient cohort,” said Dr. Jeanne Duus Johansen.
Cardiovascular risk in psoriasis – meeting a profound clinical need
Grantee: Joel Dudley, PhD, Director of Biomedical informatics, Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA, and Peter Riis Hansen, MD, DMSc, PhD, Consultant (invasive cardiology), Associate Professor, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark
Amount: DKK 13,100,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, USA
Cardiovascular diseases (CVD), such as myocardial infarction and stroke, are leading causes of death globally. Independent of traditional risk factors, however, psoriasis patients run an increased risk of CVD, adding considerably to morbidity and mortality for this large patient group.
“Inflammation has been proposed as a part of the explanation for the association between psoriasis and CVD. However, when we look at the underlying pathophysiology and molecular drivers of this connection, they are unclear. It is also unresolved whether treatment responses for psoriasis alter the course of CVD. To us, this suggests that the connection with inflammation might be more complex than currently appreciated,” said Joel Dudley, Director of Biomedical informatics at Icahn School of Medicine, Mount Sinai in New York.
Together with Peter Riis Hansen, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark, Dudley will lead a team focused on developing a much needed understanding between the molecular mechanisms of psoriasis and the increase in CVD comorbidity. Understanding these complex interactions between skin and cardiovascular health will lead to insights for future preventive treatments and improved prognosis.
The team will employ an array of modern high throughput technologies to bring together information about genetics, immunology, local gene expression, microbiomes, and more standard clinical measures to develop an unprecedented map of factors impacting cardiovascular health in psoriatic patients.
“We will apply sophisticated bioinformatics and network biology techniques to integrate the data and develop a disease network model that will enable both discovery and testing of novel hypotheses concerning biomarkers and pathogenic mechanisms. We believe that this disease network model will serve as a powerful and unprecedented resource for the dermatology, cardiology, and immunology research communities,” said Peter Riis Hansen.
More specifically, the model may facilitate the re-interpretation of data from previous studies and clinical trials, be queried by scientific and clinical investigators to evaluate novel clinical and molecular hypotheses, and inform new understanding of fundamental molecular mechanisms underlying the interplay between skin biology, immune function, and the immune-metabolic-cardiovascular axis.
The resulting disease network model may also uncover molecular mechanisms contributing to increased CVD risk in other immune disorders, such as rheumatoid arthritis, atopic dermatitis, and inflammatory bowel disease.
“We believe that the data generation activities alone would provide tremendous value to the research community, and that developments in data analysis and bioinformatics has the potential to increase exponentially our understanding of molecular mechanisms underlying CVD risk in inflammatory skin disease,” said Peter Riis Hansen.
Skin barrier function is first line of defence – Epidermal T cells dynamic, interplay and function
Grantee: Charlotte Menné Bonefeld, Associated Professor, Department of Immunology and Microbiology, University of Copenhagen
Amount: DKK 2,385,900
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark
The skin provides the first barrier of defence between the body and the environment. It is one of the largest organs of the human body and is constantly being exposed to pathogens and environmental triggers.
The outermost layer of the skin is the epidermis and it consists of a variety of both immune and non-immune cell types. Among the immune cells within epidermis are the T cells. One of the important characteristics of T cells is that they can develop into memory T cells following their activation.
Experimental work is often done with mice, but experience shows that there is difference between T cells in humans and mice epidermis – a difference that until recently has been thought related to species diversity.
Recent findings, however, have shown that environmental triggering factors, such as microorganisms or chemical irritants, lead to a dynamic shaping of the type of T cells present in the epidermis. Based on these discoveries, the team led by Charlotte Menné Bonefeld has hypothesised that the difference between T cells in human and mice epidermis are not mediated by species differences, but rather by difference in skin exposure to microorganisms and chemicals that occurs early and throughout the whole life.
Therefore, the team will investigate i) the similarities and differences of T cells in human and mice epidermis, ii) the effect of allergen and infection agents on the phenotype and activity of epidermal T cells and iii) the interplay between epidermal immune cells forming the immunological barrier properties of the skin.
Answering these questions will be crucial for developing better treatments for inflammatory skin diseases as it is very likely that these mechanisms play a central role in the pathogenesis of several inflammatory skin diseases like allergic contact dermatitis, atopic dermatitis and psoriasis.
ICR Agonists as novel therapeutics for psoriasis treatment
Grantee: Vasileios Bekiaris, Ph.D., Associate Professor, Section for Immunology and Vaccinology, National Veterinary Institute, Danish Technical University
Amount: DKK 1,047,816
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark
Psoriasis and most autoimmune diseases are characterised by a deregulated hyper activation of T cells leading to chronic tissue destruction and in many cases significant morbidity. Immune checkpoint receptors (ICRs) negatively regulate the immune system by dampening lymphocyte functionality.
Bekiaris and his team have, as have others, shown that manipulation of these ICRs can alter the outcome of the immune response; a strategy currently successful in cancer immunotherapy.
In this project the team will use the mouse psoriasis-model (IMQ) to test the hypothesis that in vivo activation of specific ICRs will block the induction and progression of psoriasis. In addition, the team aims to characterise the importance of ICR signalling during the course of psoriasis, both at the cellular and molecular levels.
The study will delineate the molecular mechanisms underlying ICR signalling during skin inflammation and potentially create a new pathway for possible future treatment of psoriasis though opening of new targets.
Analysis of epigenetic control of IL-23 expression in keratinocytes
Grantee: Dr Cord Brakebusch, Professor, Section of Molecular Pathology, BRIC, Department of Biomedical Sciences, University of Copenhagen
Amount: DKK 2,140,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark
This study seeks new targets to reduce the formation of psoriatic lesions. A novel epigenetic mechanism, which is known to induce IL-23 in psoriasis, is also found in non-lesioned skin and may hold promise.
Psoriasis is a chronic inflammatory skin disease that involves a complex crosstalk between immune cells and skin cells (keratinocytes). While the etiology of psoriasis is basically unknown, many researchers have gauged the elements of this crosstalk – in many models. During this work, they have shown that there are multiple different, yet intertwining mechanisms underlying the disease.
One is that monoclonal antibodies that target the IL-23/IL-17 immune axis have demonstrated impressive clinical efficacy in patients with moderate-severe psoriasis. There are however, still many missing pieces of the puzzle to fully understand how this disease initiates and develops.
Dr Cord Brakebusch’s team has demonstrated that keratinocyte-derived IL-23 is sufficient to cause chronic skin inflammation in mice. Furthermore, they have elucidated an epigenetic mechanism which controls IL-23 expression and it is explained that the epigenetic control mechanism has been shown not just in active psoriasis lesions, but also, albeit to a lesser extent, in normal-appearing skin of psoriasis patients.
This suggests that the epigenetic alterations might precede the development of psoriasis lesions, and the team now wants to identify and validate targets for small molecule drugs that may prevent excessive IL-23 expression by keratinocytes through this epigenetic mechanism.
As a long-term goal for the study and its potential findings Dr Brakebusch and his team hope that topically administrated small molecular weight inhibitors could prevent excessive IL-23 production by keratinocytes – and ultimately aim at reducing the formation of psoriatic lesions.
Big Bang – support for Denmark’s largest science conference
Grantee: Astra, the national Centre for Learning in Science, Technology and Health in Denmark, Copenhagen
Amount: DKK 2,000,000
Grant category: Education and Awareness Grants
Year: 2016
Geography: Denmark
Denmark’s largest science conference, the Big Bang Conference, has received two million Danish kroner over the next three years from the LEO Foundation.
Big Bang is the largest Danish science conference and exhibition targeted all who teaches, facilitates or researches in the science and science fields – in primary and secondary schools and higher education.
The conference, held once a year, gathers more than 1,000 people for two involving and inspiring days with relevant keynote speakers, a humming exhibition atmosphere, involving workshops and novel ideas for the continued renewal of science education.
The conference is held next on 23 and 24th March 2017 in Odense Congress Center, Denmark.
Young Scientists
Grantee: Mikkel Bohm, Young Scientists (Astra)
Amount: DKK 3,000,000
Grant category: Research Grants in open competition
Year: 2015
Geography: Denmark
The talent competition, Young Scientists, is developing talents in both kids and young people in science.
It is believed that science is a powerful tool to understand and change the world for the better. The competition’s aim is to contribute to society in a meaningful way by inspiring a new generation and giving them engaging experiences with science.
The LEO Foundation has found this work important and supports the competition over three years.
LEO Foundation Center for Cutaneous Drug Delivery
Grantee: Department of Pharmacy, University of Copenhagen
Amount: DKK 40,000,000
Grant category: Standalone grants
Year: 2015
Geography: Denmark
Understanding how drugs interact with skin has long been a challenge within pharmaceutical research. Now, a new center at the Department of Pharmacy, UCPH, is set to become an international lighthouse in this research area, supported by a DKK 40 million grant from the LEO Foundation.
The LEO Foundation Center for Cutaneous Drug Delivery will form the basis of new research on skin and drugs. Behind the project is the Department of Pharmacy at the University of Copenhagen, where the center will also be located. The Director of the new center, Martin Malmsten, was formerly Head of Research at Uppsala University.
“I hope to contribute with my experience and thus help motivate and inspire colleagues and employees, enabling us to provide the best possible results. At the same time, I look forward to becoming part of the University of Copenhagen, where they have been very willing to prioritize strategic focus areas. The new center offers great and long-term opportunities for making an impact on international research and I’m happy to be part of this initiative, which will lift research in a very exciting area,” said Martin Malmsten.
The LEO Foundation Center for Cutaneous Drug Delivery will conduct research on what happens in and on the skin when we apply drugs. There will be a particular focus on the physical-chemical aspects of the interaction between skin and drugs, which is important to the development of new drugs. This will hopefully help optimize the drug properties and allow for maximum utilization while simultaneously minimizing side effects.
“Our new center meets a huge demand for understanding how drugs interact with skin. With a strong team of highly qualified researchers, we will set new standards for research in the field of dermatology and I’m both proud and grateful that this grant from the LEO Foundation has helped us attract new and strong forces to UCPH. This new strategic effort will benefit patients as well as society in general,” said Dean Ulla Wewer from the Department of Health and Medical Sciences at the University of Copenhagen.
Generating new knowledge while also providing a space for innovative research methods and new analytical technologies is what the center aims for. The LEO Foundation has backed the center with a grant of DKK 40 million over the next ten years, which in itself is quite remarkable.
“We’re very happy to support this important initiative and the grant of DKK 40 million over the next ten years is the single largest grant the foundation has ever awarded. What’s more important, however, is the fact that we are quite convinced that the center with its strong team of researchers has the potential to become a global powerhouse in terms of research on the dynamic interaction between drugs and skin,” said Lars Olsen, Chairman of the LEO Foundation.