Explore our grantees and awardees

Grant category: Research Grants in open competition

Year: 2019

Geography: USA

The overarching goal of this grant is to better understand the origins of melanomas that appear suddenly, or de novo.

Approximately 70% of melanomas appear in this way, while the remainder grow out of preexisting nevi. Nevi can be monitored and prophylactically removed if they show signs of change, but melanomas that arise de novo are impossible to foresee. It is therefore of utmost importance to understand the origins of melanomas that appear de novo in order to develop biomarkers to predict their emergence.

We previously sequenced melanomas adjacent to nevi, revealing two classes of mutations – initiating mutations (emerging in nevi) and progression mutations (emerging in melanoma). Here, we hypothesize that progression mutations can precede initiating mutations. In this scenario, a melanocyte silently accumulates progression-associated mutations, followed by an initiating mutation so that the ensuing neoplasm ‘skips’ the precursor stages, manifesting directly as a melanoma.

If validated, this hypothesis would explain how de novo melanomas evolve. Here, we will genotype individual melanocytes from healthy human skin to test whether morphologically normal melanocytes can harbour progression mutations. Towards this goal, we have developed innovative solutions to establish high-quality genotyping calls from individual cells. In our preliminary data, we genotyped 17 melanocytes collected from healthy skin, and pathogenic mutations were surprisingly common, supporting our hypothesis. We will extend these studies to fully delineate the spectrum of cancer-associated mutations in melanocytes from healthy skin.

Overall, completion of these studies will reveal the origins of melanomas that do not pass through a precursor stage – a longstanding goal in the skin research community.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

Neurofibromatosis type 1 (NF1) is a progressive genetic disorder characterized by changes in skin and growth of tumors along nerves in the skin and other parts of the body.

The clinical signs of NF1 are well‐described, but the impact of NF1 on the daily life and the burden of treatment is less studied.

By combining data from nationwide registries and questionnaires, we will assess drug use and surgery in individuals with NF1, socioeconomic consequences of living with NF1 as well as predictors of quality of life. Patients with NF1 are identified in the Danish National Hospital Register and from two National Centers of Rare Diseases at Copenhagen University Hospital, Rigshospitalet, and Aarhus University Hospital.

Outcomes in 2,517 individuals with NF1 (drug use, surgical procedures, employment status, income, social security benefits and ninth school grades) will be compared to those in a healthy comparison group. In a sub‐group of 244 adults with NF1, we will examine how these specific outcomes will impact quality of life. Individuals with NF1 are particularly vulnerable for a lower living standard and prosperity with extensive costs for the society.

We believe that the results of these studies will add a major contribution to the NF1 research field as well as improve our understanding of the implications this complicated disease may have on life. The clinical information provided by these large nationwide studies is highly requested by the patients and their families but also by the clinicians advising these patients.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

Psoriasis affects 2-4% of the Western adult population and is a socio-economic burden for patients and society.

Topical drugs are recommended as first-line treatment for mild to moderate psoriasis, but low adherence is a barrier for treatment success.

There is a need for improved patient support for psoriasis patients, which is suggested to improve long-term use of topical drugs.

The project aims to test whether a patient-supporting intervention delivered by healthcare professionals can improve the use of topical drugs.

The intervention design is based on experiences with previous adherence-improving studies consisting of digital support by conducting a systematic literature search and holding focus groups with patients as well as healthcare professionals. The intervention consists of shared decision-making with patients, nurses and doctors, frequent consultations, easy access to healthcare professionals through video or in-office consultations and holding patients accountable for taking the medication.

The intervention will be tested in a randomized controlled trial: during a 1-year period, a group of patients (18-75 years of age) diagnosed with mild-to-moderate psoriasis and treated with topical drugs will be randomized to an intervention (n=65) or non-intervention group (n=65).

The primary outcome will be primary adherence (i.e., rate of filled prescriptions) and secondary outcomes a reduction in the severity of psoriasis and cost-effectiveness. If the intervention can reduce the severity of psoriasis in a significant manner and is cost-effective, there is a potential for a national implementation of the intervention.

Grant category: Standalone grants

Year: 2019

Geography: Denmark

Researchers in immunology, cell biology and cancer were first movers in single-cell sequencing when they demonstrated a huge potential of this novel technology to unravel novel cell populations and disease heterogeneity.

This approach has gained further momentum fueled by new, exiting studies in neurobiology and rheumatology. So far, single-cell sequencing has not been used in relation to skin diseases – with few exceptions such as our new study on single-cell sequencing in cutaneous T cell lymphoma (CTCL) – the first paper of its kind – which was rapidly followed by three additional papers on single-cell sequencing in CTCL.

Moving from investigating an average of molecular changes in thousands or millions of cells to the study of changes in the transcriptome in single cells is critical to obtain a deeper and more precise understanding of disease heterogeneity and novel disease mechanisms. In other words, single-cell sequencing is expected to become the novel golden standard in all areas of research related to immunology and inflammation including the scientific focus area of the LEO Foundation Skin Immunology Research Center.

The “package” provides the sufficient capacity to conduct state-of-the-art single-cell analysis in the key areas of the LEO Foundation Skin Immunology Research Center. In order to get maximal advantage, value, and rapid implementation of the instruments, we will employ a novel protocol for this platform to run up to 5 different modalities (mRNA, TCRab, TCRgd, surface proteins, sample hashing and CRISPR lead sequences) in parallel to top-tune the technology.

Grant category: Research Grants in open competition

Year: 2019

Geography: Spain

Targeting ZEB1 in macrophages as a new therapeutic approach to psoriasis.

Psoriasis involves deregulation of the innate and adaptive immunities. The metabolism of T cells as well as of keratinocytes is altered in psoriasis. Metabolism also controls the immunogenic versus tolerogenic responses of macrophages through mechanisms still not fully understood.

Our preliminary data indicate that: 1) the transcription factor ZEB1 is downregulated in the skin of psoriatic patients and of mouse models of psoriasis as well as in the peripheral blood monocytes/macrophages of psoriatic patients; 2) ZEB1 expression in macrophages ameliorates psoriatic lesions in mice; 3) Mechanistically, ZEB1 regulates macrophage tolerogenic responses in psoriasis by inhibiting mitochondrial activity and reducing pro-inflammatory cytokines and ROS.

The project will investigate: 1) the molecular mechanisms by which ZEB1 modulates macrophage response in psoriasis; 2) the expression, role, and mechanism of action in psoriasis of the related factor ZEB2, which has opposing roles to ZEB1 in other contexts; 3) ZEB factors in macrophages as therapeutic targets in psoriasis.

Implementing this project will be impactful as it will explore a new pathogenic mechanism and inform the design of safer and more targeted therapies to improve the quality of life of psoriatic patients. The proposal is innovative both conceptually—proposing unexpected immunoregulatory roles for ZEB1/2—and methodologically—using unique mouse models and bridging macrophage biology, gene regulation, and metabolism.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

Long-term topical application of steroids such as hydrocortisone have severe skin side effects. Here treatments lead to thinning of the outer layer of the skin, reduced production of natural moisturisers and an increased risk of skin ulceration.

We hypothesise that an increased understanding of how hydrocortisone exerts its effect on skin cells will help us understand why hydrocortisone treatment causes these adverse effects and also aid the development of treatments that can bypass these.

Here we propose to take advantage of exciting new methods we have developed, where we can measure how cells behave within the skin and thereby quantify exactly how hydrocortisone affects cell turnover. This analysis will be combined with detailed studies for how hydrocortisone function at the mechanistic level in order to identify potential new therapeutic targets. Such therapies could be used to help patients receiving long-term hydrocortisone treatment.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

This project focuses on development of 3D bio-printed physiologically accurate human skin, which has important applications both clinically and for research.

3D printed human skin can be used in pharmacological and cosmetic testing, disease modelling, basic skin biology research, but also it can potentially save lives by providing skin grafts for burn or accident victims.

However, the current 3D printed skin is frail and prone to rupturing and does not recapitulate the native tissue. By combining quantitative imaging of intracellular junctions and cytoskeletal components at the sub-cellular, cellular and tissue levels in a rapid in vivo model and human 3D skin cell culture with direct measurements of tissue stiffness, we will deliver the most detailed description yet of the mechanical regulation and barrier properties of the skin.

Next, we will determine how the mechanical properties of skin change upon application of physical stimuli and if we could imitate the mechanical response by molecular perturbations.

Finally, we will identify and verify novel molecular players that set the mechanical properties of skin by unbiased single-cell sequencing of fragile and elastic tissues.

These results will be used to develop artificial 3D skin which more accurately represent human skin than current models. This interdisciplinary proposal is a crucial step forward in entering an era where animal experiments and transplants are replaced by synthetic organs printed for patients on demand.

Grant category: Research Grants in open competition

Year: 2019

Geography: Sweden

Skin is the largest human organ and contains an intricate variety of cell types that assure tissue architecture and proper skin function, such as thermoregulation and hair growth.

An imbalance of cell types and/or molecular signalling often results in disease. Across the body, skin composition differs in thickness, hair growth, sebaceous and sweat gland density, microbiota exposure and disease susceptibility.

However, a molecular understanding of how cell types and genetic programs vary with skin regions, and molecular alterations in disease, is currently lacking.

Previously, my lab pioneered the use of single-cell RNA-seq (scRNA-seq) in mouse skin by generating a comprehensive molecular and spatial atlas of epithelial and mesenchymal cells during hair growth and rest (Joost et al. 2016; Joost et al. 2019). Building upon our expertise, we will molecularly dissect human skin, initially through a body map that spans various body sites of healthy donors, to identify cell types and sub types in human skin and also to investigate important cell type differences and alterations compared to mouse skin. Subsequently, the body map will be the foundation for molecular analyses of skin diseases, including immune-triggered psoriasis.

A carefully constructed and annotated human skin atlas, with spatial and molecular precision, would have enormous value for the scientific community and propel our molecular understanding of skin in health and disease.

Grant category: Education and Awareness Grants

Year: 2019

Geography: Denmark

Bloom – at the core:

Bloom is an innovative festival about science and nature, which enlighten us on the Universe, the World and Ourselves. Framed in the lush Søndermarken at Frederiksberg in the heart of the capital city of Denmark, where some of the World’s greatest scientists, poets and philosophers have found inspiration through history, Bloom emerges each Spring as a sensual, experimental and thought-provoking festival version of natural sciences.

By uniting the best from the world of festivals with the best from the scientific world, Bloom arm wrestles with Life’s greatest questions and over two days invite the audience to debates, talks, laboratories, conversations and nature walks under open skies.

Grant category: Research Grants in open competition

Year: 2019

Geography: United Kingdom

There is a sterile inflammatory response to needle challenge driven by recruitment of inflammatory monocytes to the skin in old humans. This inflammatory response negatively correlates with cutaneous immunity after injection of varicella zoster virus antigens into the skin. Inhibition of the inflammation associated with the injury response, with a p38-MAPkinase inhibitor, reduced inflammatory monocyte recruitment and significantly enhanced antigen-specific immunity.

The aim of this project is to understand how inflammation and inflammatory monocytes inhibit antigen-specific T cells in the skin of old human volunteers.

The following experimental questions will be addressed: 1) Which cells are responsible for the inflammatory response to needle injury and how does the interaction between the infiltrating monocytes and other inflammatory populations amplify the response? 2) How are the inflammatory monocytes recruited to the site of challenge in the skin? 3) How do the recruited monocytes inhibit antigen-specific immunity in vivo in the old? 4) Using biobanked skin biopsy samples before and after the same older subjects have been treated with Vitamin D, we will determine gene expression signatures of how this treatment enhances cutaneous antigen-specific immunity.

These investigations will identify ways to enhance the immunity of older humans to vaccination and also infection and malignancy.