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.

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.

Psoriasis in children

Grantee: Professor Lone Skov, Department of Dermato-Allergology, Gentofte Hospital

Amount: DKK 4,500,000

Grant category: Research Grants in open competition

Year: 2014

Geography: Denmark

Psoriasis is a chronic inflammatory skin condition with a prevalence of 2-3% in northern Europe. While considerable research exists on adults with psoriasis, there is little research on the condition in children. Identifying key factors associated with psoriasis in childhood may lead to more effective control and possibly even prevention of the condition.

The study aims to determine environmental and genetic risk factors relating to the development of psoriasis in children, the nature of stress related to the child and family, and quality of life. The project also aims to determine the link with risk factors of co-morbidity and the effect of early intensive treatment.

The study is led by Professor Lone Skov, Department of Dermato-Allergology, Gentofte Hospital, Denmark. The team will explore the following hypotheses:

  • Risk factors for early onset of psoriasis can be predicted
  • Early debut of psoriasis has a significant impact on quality of life and individual and family-related stress
  • Early intensive treatment leads to remission
  • There is already an increased risk of co-morbidity in children with psoriasis
  • Age at debut, risk factors and co-morbidity are related
    to the genetic risk.

The study offers a unique possibility to access data from children with psoriasis shortly after diagnosis, which in turn can pave the way for new and improved tools for assessing the impact of the condition on quality of life in a well-controlled study design.

Psoriasis and cardiovascular co-morbidity – epidemiological and experimental studies

Grantee: Dr Peter Riis Hansen, Department of Cardiology P, Gentofte Hospital

Amount: DKK 4,200,000

Grant category: Research Grants in open competition

Year: 2012

Geography: Denmark

Psoriasis patients have increased risk of cardiovascular disease (CVD), which still carries high morbidity and mortality in western societies, and is increasing dramatically in the emerging economies.

Consequently, research directed at the interface between psoriasis and CVD, from the level of epidemiological studies to basic experimental research, is of paramount importance in order to improve overall care for psoriasis patients, as well as supporting the need to seek help to receive treatment.

A research project led by Dr Peter Riis Hansen, Gentofte Hospital, Department of Cardiology P, Denmark, will help to:

  • Inform and motivate dermatologists to play a pivotal role in screening and helping patients with psoriasis to prevent an increased risk of CVD
  • Motivate patients with psoriasis to, firstly, seek treatment and assessment of their CVD risk and, secondly, improve treatment of psoriasis to reduce the overall immune activation
  • Establish a murine model of psoriasis and CVD that is suitable for mechanistic studies and preclinical drug evaluation
  • Identify new markers of psoriasis and/or CVD activity that may be relevant for clinical use.

Publications:

Khalid U et al. Psoriasis and new-onset diabetes: a Danish nationwide cohort study. Diabetes Care 2013;6:2404-7

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714512/

Khalid U et al. Psoriasis and risk of heart failure: a nation-wide cohort study. Eur J Heart Fail 2014;16:743-8

http://www.ncbi.nlm.nih.gov/pubmed/24903077

Khalid U et al. Sarcoidosis in patients with psoriasis: a population-based cohort study. PLoS ONE 2014;9(10)e109632

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186869

Khalid U et al. Increased risk of aortic valve stenosis in patients with psoriasis: A nation-wide cohort study. Eur Heart J 2015;36:2177-83

http://eurheartj.oxfordjournals.org/content/36/32/2177.long

Khalid U et al. A nationwide study of the risk of abdominal aortic aneurysms in patients with psoriasis

http://atvb.ahajournals.org/content/36/5/1043.long

Madsen M et al. Effects of TPA-induced experimental psoriasis-like skin inflammation in atherosclerosis-prone apoE knock-out mice. BMC Dermatology 2015

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940745

Epidemiology of eczema disease in Denmark

Grantee: Professor Torkil Menné and Professor Jeanne Duus Johansen, Gentofte Hospital

Amount: DKK 2,828,000

Grant category: Research Grants in open competition

Year: 2012

Geography: Denmark

The project involves several research groups at Gentofte Hospital in Copenhagen and is headed by Professor Torkil Menné and Professor Jeanne Duus Johansen.

The work aims to shed more light on the incidence of eczema in the general population and pave the way for improved prevention and treatment.

Eczema is the most prevalent of the skin disorders. It is not only one of the most common childhood diseases, but also a typical occupational disease, making it one of the most widespread diseases in the overall population. Eczema also results in substantial costs and loss of quality of life for patients.

Despite the disease prevalence, there is a shortage of data and research on eczema in the general population.

This project, which draws on a number of databases and disease registries unique to Denmark, aims to produce a detailed picture of the clinical and sociodemographic aspects of eczema in both the general population and the patient population.

Its specific aims are:

  • To describe the consequences of eczema in terms of health care, education and employment, and the development of co-morbidities
  • To explore the genetics behind eczema and its
    consequences.

Publications:

Anatomical patterns of dermatitis in adult filaggrin mutation carriers

J Am Acad Dermatol. 2015 Mar;72(3):440-8. doi: 10.1016/j.jaad.2015.01.001. Epub 2015 Feb 7

Predictive factors of self-reported hand eczema in adult Danes – a population based cohort study with 5 year follow-up

Br J Dermatol. 2016 Aug;175(2):287-95. doi: 10.1111/bjd.14476. Epub 2016 May 24

Health-related quality of life in adult dermatitis patients stratified by filaggrin genotype

Contact Dermatitis. 2017 Mar;76(3): 167-177. doi: 10.1111/cod.12731. Epub 2016 Dec 16 

Hand eczema, atopic dermatitis and filaggrin mutations in adult Danes: a registry-based study assessing risk of disability pension

Contact Dermatitis. 2017 Aug;77(2):95-105. doi: 10.1111/cod.12786. Epub 2017 Apr 20

The LEO Foundation Scholarship for Dermatological Research

Grantee: Scholarship programme

Amount: DKK 2,200,000

Grant category: Research Grants in open competition

Year: 2012

Geography: Australia, Denmark

The LEO Foundation Scholarship for Dermatological Research aims to strengthen research collaboration within the field of skin cancer between Australia and Denmark by supporting training of and research by young scientists.

One scholarship is offered annually on behalf of the LEO Foundation, alternating between Australia and Denmark.

A candidate from Australia travels to work within a Danish tertiary institution and a Danish student is selected with a view to joining an Australian campus.

The funds received may be used as part of an ongoing PhD project or for postdoctoral research. The funds must in part support a research/educational stay in Australia of at least six months for the Danish student.

Publications

Automated detection of actinic keratoses in clinical photographs

Hames SC, Sinnya S, Tan JM, Morze C, Sahebian A, Soyer HP, Prow TW.

PLoS One. 2015 Jan 23;10(1):e0112447. doi: 10.1371/journal.pone.0112447. eCollection 2015

Counting actinic keratosis – is photographic assessment a reliable alternative to physical examinations in clinical trials?

Sinnya S, O’Rourke P, Ballard E, Tan JM, Morze C, Sahebian A, Hames SC, Prow TW, Green AC, Soyer HP.

Acta Derm Venerol. 2015 May;95(5):604-5. doi: 10.2340/00015555-2040. No abstract avaliable

The future of keratinocyte skin cancer surveillance: automated image analysis to identify and monitor keratinocyte dysplasia

Hames SC, Prow TW.

Curr Probl Dermatol. 2015;46:77-84. doi: 10.1159/000366540. Epub 2014 Dec 18

Automated segmentation of skin strata in reflectance confocal microscopy depth stacks

Hames SC, Ardigò M, Soyer HP, Bradley AP, Prow TW.

PLoS One. 2016 Apr 18;11(4):e10153208. doi: 10.1371/journal.pone.0153208. eCollection 2016.

Automated detection of actinic keratoses in clinical photographs

Hames SC, Sinnya S, Tan JM, Morze C, Sahebian A, Soyer HP, Prow TW.

PLoS One. 2015 Jan 23;10(1):e0112447. doi: 10.1371/journal.pone.0112447. eCollection 2015.

Counting actinic keratosis – is photographic assessment a reliable alternative to physical examination in clinical trials?

Sinnya S, O’Rourke P, Ballard E, Tan JM, Morze C, Sahebian A, Hames SC, Prow TW, Green AC, Soyer HP.

Acta Derm Venereol. 2015 May;95(5):604-5. doi: 10.2340/00015555-2040. No abstract available.

The future of keratinocyte skin cancer surveillance: automated image analysis to identify and monitor keratinocyte dysplasia

Hames SC, Prow TW.

Curr Probl Dermatol. 2015;46:77-84. doi: 10.1159/000366540. Epub 2014 Dec 18

Anatomical skin segmentation in reflectance confocal microscopy with weak labels*

Hames SC, Ardigò M, Soyer HP, Bradley AP, Prow TW.

http://ieeexplore.ieee.org/xpls/abs_aa.jsp?arnumber=7371231&tag=1

* This won the Canon Extreme Imaging Competition (DICTA category) prize in late 2015