Grantee: David Granville, Professor, University of British Columbia, Canada

Amount: DKK 2,023,506

Cutaneous leishmaniasis (CL) is a World Health Organization top neglected tropical disease, with up to 1 million new cases worldwide annually.

CL is an inflammatory skin disease caused by infection with Leishmania parasites that lead to tissue damage, ulcers, and severe scarring, despite current treatment options. Granzyme B (GzmB) is a protein that is aberrantly elevated in CL lesions and other inflammatory skin conditions. GzmB activity has been demonstrated to cleave important proteins in the skin, exacerbating tissue damage, delayed wound healing, and scarring in inflammatory patient skin specimens and in experimental models. Importantly, inhibition of GzmB have shown efficacy in impeding these disease phenotypes. In recent years, accumulating reports have linked GzmB expression and activity to disease severity measures of CL but GzmB’s functional role is unexplored.

Herein, we hypothesize that in CL lesions, GzmB contributes to inflammation, impaired wound healing, and scarring that can be averted by a GzmB inhibitor. To test this hypothesis, our 3-pronged approach will include lesional specimens from CL patients, a well-established experimental model to study GzmB function, and a GzmB inhibitor, Serpina3n. Together, the proposed study findings will provide key rationale to pursue GzmB as a novel therapeutic target for the treatment of CL.

Grantee: Jeppe Madura Larsen, Senior Researcher, Technical University of Denmark, Denmark

Amount: DKK 4,349,062

Atopic dermatitis (AD) is a common inflammatory skin disease affecting 15% of children and 3-5% of adults. AD is associated with the risk for developing co-morbidities such as other atopic diseases (food allergy, asthma, and rhinitis) and infections. Co-morbidities are believed to occur because of functional changes in the immune system of AD patients. However, it remains unknown how these changes are established. Emerging experimental studies suggest the existence of a skin-gut immune axis, but the role for the gut remains largely unexplored in AD.

We hypothesize that AD drives dysregulated immune responses to the gut microbiota, which in turn changes the immune system giving rise to atopic comorbidities and risk for infections.

In other words, we envisage that AD patients become “allergic” to the bacteria present in their intestine – leading to a “persistent allergic reaction” due to continuous presence of bacteria in the intestine.

This project will use a rat model to determine if AD changes gut microbiota composition and function, alters the intestinal and systemic immune system, and increases the risk for food allergy co-morbidity via oral sensitization.

We will perform a human case-control study to support the clinical relevance of the findings established in the rat model. Identification of bacterial drivers of persistent type-2 inflammation could open new avenues for the prevention and treatment of AD and related co-morbidities.

Grantee: Vasileios Bekiaris, Associate Professor, Technical University of Denmark, Denmark

Amount: DKK 2,815,499

Psoriasis affects 2–3% of the world’s population, causes scaly, red, itchy and painful skin patches which can occur in any part of the body (hands, face, skull). Moreover, psoriasis patients have a high risk of developing secondary arthritis.

Psoriasis is an inflammatory disease caused by overproduction of tissue-damaging cytokines by immune cells and keratinocytes. Central cytokines in this disease are TNF and IL-17, which are currently approved therapeutic drug targets. However, such therapies often do not work and it is therefore important to better understand the biology of TNF and IL-17 in relation to psoriasis. We have shown before that two enzymes known as cIAPs can alter the sensitivity of immune cells to TNF and thus suppress production of IL-17.

In this project, we hypothesize that cIAPs play a central role in psoriasis by modulating the response of the immune system and of keratinocytes to TNF in order to fine-tune IL-17 production. More specifically, we will investigate whether deficiency of cIAPs or their pharmacologic inhibition makes the immune response less pathogenic and alleviates the pro-inflammatory nature of keratinocytes during psoriasis. To achieve this, we will use genetic mouse models in combination with human culture techniques.

Knowledge gained by this study will provide novel biological information of how psoriasis develops and progresses and may provide additional means to improve current therapies.

Grantee: Salvador Aznar Benitah, Professor, Institute for Research in Biomedicine in Barcelona, Spain

Amount: DKK 204,130

The 2021 Gordon Research Conference on Epithelial Differentiation and Keratinization is the premier international meeting in epithelial biology since 1979. The goal of the 2021 meeting entitled “Novel mechanisms of regulation in epithelial biology and their implication in physiology, aging and disease” is to foster eminent speakers at the forefront of areas such as immunity, tissue sensing and cross-talk, genomics and epigenomics, and novel technologies to drive therapy.

The meeting will promote intense interactions among these disciplines and discovering novel therapeutic prospects to advance the field. To ensure this, 20% of speakers are from outside the immediate field, 85% did not speak in 2019, and over 30% will be selected from abstracts. A power hour will open a debate on tackling discriminations in science, and for the first time there will be a related talk in one of the main sessions. Trainee mentorship will be promoted through the associated Gordon Research Seminar which is organised by trainees providing a unique opportunity to discuss their research and develop collaborations. It will feature a mentoring session on transitioning to independence, and career opportunities in academia and industry.

Collectively, this GRC/GRS will move forward cutting-edge research in skin biology, promote translation of key findings to clinical practice, and further the careers of early stage investigators to maintain the highest level of innovation of this field in the future.

Grantee: Professor Chris Griffiths, University of Manchester, UK

Amount: DKK 8,000,000

Psoriasis is a significant, life-long and currently incurable skin disease, which, according to the first edition of the Global Psoriasis Atlas (GPA), affects at least 60 million people worldwide.

The need to understand and uncover how psoriasis impacts both the individual and society at large is in demand. The Global Psoriasis Atlas is a long-term project that seeks to become the ‘go-to’ evidence-based resource within the understanding of psoriasis and its effects on people and society all over the World.

GPA Phase II (2020-2023)

The GPA Phase II  is focused on continued research to establish robust data that address existing knowledge gaps within psoriasis on epidemiology, improving diagnosis, comorbid disease and economic impact.

Furthermore, if sufficient and robust data are available, the plan is to perform a pilot implementation study as part of GPA Phase II.

Addressing these key areas and how they differ between countries and regions will support the aim to provide better access to care for people with psoriasis worldwide.

Background

With a mission to ‘ensure that people with psoriasis, wherever they live in the world, have access to the best available care. The grant for the first version of the GPA was granted to Professor Griffiths and the University of Manchester in 2016.

The LEO Foundation has been main funder of the development of the first edition of the GPA through a 3-year grant of DKK 6,370,000 from 2017 – 2020. The GPA project has in its first three years focused on research into the global prevalence and incidence of psoriasis – resulting in the first edition of the GPA website which can be accessed free of charge here: Global Psoriasis Atlas online

 

Grantee: Sergei Koralov, Associate Professor, NYU Langone, NY, USA

Amount: DKK 2,676,248

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of blood-related cancers characterized by chronic inflammation and accumulation of malignant T cells in the skin.

The most common variant of CTCL, mycosis fungoides (MF), is often indolent in its early stages and can be managed by topical agents. However, advanced stages of MF and the systemic variant of the disease, Sezary syndrome, have a more aggressive clinical course, prove difficult to treat, are debilitating, and have no cure. CTCL is characterized by hyperactivation of the gene regulator STAT3.

We and others demonstrated the critical role of this pathway in maintaining malignant T cells. Our proposed experiments build on a recent finding that atovaquone, a well-tolerated anti-microbial drug, inhibits STAT3 signaling in mammalian cells.

We found that atovaquone triggers cell death and selectively inhibits growth of patient derived CTCL tumor cells. We now propose to use our fully penetrant animal model of this disease and primary patient cells to define precisely how atovaquone inhibits STAT3 in vivo, to establish the potential of atovaquone to treat CTCL.

The proposed studies will provide new insight into the pathogenesis of this disease and provide better understanding of the mechanism of action of this drug.

Given atovaquone’s outstanding safety and tolerability profile, the drug holds tremendous potential for the treatment of malignant and inflammatory diseases characterized by aberrant STAT3 signaling.

Grantee: Edwin En-Te Hwu, Associate Professor, Technical University of Denmark, Kgs. Lyngby, Denmark

Amount: DKK 2,824,593

The severity of atopic dermatitis (AD) is closely correlated to skin barrier.

In recent years, the nanoscale anatomy (nanotexture) on corneocytes surface was explored through atomic force microscopes (AFMs), hinting.

The number of circular nano-objects yielded a biomarker called dermal texture index (DTI). Furthermore, clinical studies revealed that the DTI is closely associated with skin barrier function.

AFMs can measure tape-stripped corneocytes nanotexture without any sample preparations. However, conventional AFMs suffer from low throughput at a high cost and limited usability in a clinical setting.

Recently, we have pioneered a unique AFM technique and we would like to integrate DTI analysis for skin barrier function assessment. This project aims to develop a tailor-made Dermal AFM that has ten times higher throughput than conventional AFMs and is easy to use in clinical environments.

The project is coordinated from DTU Health Technology and is performed in collaboration with hospitals in Denmark, Netherlands and Taiwan for AD severity assessment and skin sample acquisition.

Different regions AD nanotexture data (Europe and Asia) facilitate optimization of DTI to assess AD in a subclinical phase, as well as courses and pharmacotherapy effectiveness quantitatively. The Dermal AFM may also, in future research projects, pave the way for unveiling the science behind the corneocyte nanotexture formation.

Grantee: Andor Pivarcsi, Associate Professor, Uppsala Universitet, Uppsala, Sweden

Amount: DKK 4,164,300

Cutaneous Squamous Cell Carcinoma (cSCC) is the most common and fastest-increasing cancer with metastatic potential, which accounts for 20% of all skin cancer-related deaths.

Patients with advanced tumors lack efficient treatment options, thus, there is an urgent medical need to find novel therapeutic approaches.

Long noncoding RNAs (lncRNAs) represent a crucial but as yet largely unexplored layer of gene regulation. We hypothesize that alterations in lncRNA-networks contribute to malignant progression and the that modulation of lncRNA expression can have therapeutic relevance.

Recently, we have performed a comprehensive RNAseq analysis in cSCC and identified a set of novel lncRNAs with altered expression in cSCC and whose functions are poorly characterized or completely unknown. These lncRNAs represent potential regulators of epidermal homeostasis and carcinogenesis.

In this study, we will explore the function of the identified lncRNAs in loss- and gain-of-function studies using in vitro and in vivo experimental models of cancer and differentiation, in vivo modulation of lncRNA-activity by delivery of antisense oligonucleotides (ASOs).

Additionally, we will identify the pathways regulated by cSCC-associated lncRNAs and define their mechanism of action by the biochemical characterization of binding partners.

Results of the proposed project will reveal the role of lncRNAs in epidermal carcinogenesis and pave the way towards the use of ASO-based be therapy of skin cancer.

Grantee: Peter Arkwright, Senior Lecturer, The University of Manchester, United Kingdom

Amount: DKK 4,369,423

Atopic eczema is the most common skin disease in many Western countries. Although considered an allergic disease, skin infections with S. aureus are an important cause of eczema flares. In the skin of patients suffering from eczema S. aureus predominate over “good bacteria” such as S. epidermidis (S. epi).

We work on human eczema at the University of Manchester, UK and our collaborators at TUAT University, Tokyo, Japan study a unique NC strain of mouse prone to getting eczema very similar to that seen in humans.

Together over the last 3 years, we have discovered a single factor produced by S. aureus that causes eczema in both humans and mice. We have also found that S. epi prevents the eczematous inflammation by S. aureus.

We now want to work out the exact nature of the factor produced by S. epi that prevents eczema in our system.

Using the methods, we employed in our previous collaborative study, we plan to isolate and identify the factor produced by S. epi based on its size and structure using separation columns and mass spectrometry.

We will then manipulate the genome of S. epi to confirm its identity. Finally, we will determine how the factor blocks S. aureus-driven eczema by studying how it affects S. aureus growth, as well as binding and interaction with skin cells.

Identifying this S. epi-derived factor could lead to the development of new medicines for the treatment of eczema.