Explore our grantees and awardees

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

Epidermal renewal and keratinocyte differentiation are pivotal for skin homeostasis and maintenance of the skin’s barrier function, which is impaired in inflammatory skin diseases.

Expression of dermokine, a member of the stratified epithelium secreted peptides complex, is highly upregulated under these conditions, but its functional contribution to epidermal stratification and differentiation remains largely elusive.

We have identified dermokine as a substrate of the wound- and tumor-related matrix metalloproteinase (MMP) 10 in vitro and in vivo, a proteolytic processing event that might play a role in maintaining the phenotype of transient amplifying keratinocytes in hyperproliferative epidermis.

In this project, we will characterize the activity of dermokine and analyze its putative function in keratinocyte differentiation. Using advanced proteomics, we will identify surface binding proteins for dermokine on keratinocytes. Newly identified dermokine-receptor interactions will be characterized and related to signaling pathways that are activated in response to dermokine binding.

To test the hypothesis that MMP10 modulates dermokine activity, we will analyze the full-length protein in comparison to a truncated mutant, resulting from MMP10 cleavage. This mutant will be characterized for altered effects on keratinocyte differentiation, binding to receptor candidates and activation of downstream signaling.

This study will provide insight into the function and mechanisms of action of dermokine in normal and hyperproliferative epithelia and add to current knowledge on MMPs as modulators of extracellular signaling ligands in the skin. Anticipated results will help to devise new strategies for therapeutic intervention with barrier defects in inflammatory skin diseases.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

The skin microbiome has been thought to be highly individual, a kind of ‘microbial fingerprint’.

Yet scratching beneath the surface with DNA metabarcoding different skin compartments, we have found considerably less variation in the bacterial communities of the dermal compartment compared to the outer epidermal, challenging this dogma.

Here, we will extend upon these findings by performing a more comprehensive shotgun metagenomic approach, assessing whether compositional differences in the dermal and epidermal microbiomes effect their functioning.

The invasiveness of biopsies has been a major limitation in sampling of dermal microbiomes. Tape-stripping is a minimally invasive technique that penetrates through the epidermal compartment to the barrier with the dermis, and here we assess whether tape-stripping can substitute biopsies in accessing the potentially more informative, less environmentally variable skin microbiomes.

Finally, we will compare the dermal microbiomes of healthy controls to patients suffering atopic dermatitis (AD). Sufferers of AD have been repeatedly shown to have a perturbed epidermal microbiome, but they also have perturbed immune systems. Here we perform shotgun metagenomic and metatranscriptomic approaches to test for functional differences between the microbiomes of AD patients and healthy controls.

Studying the differences between healthy and diseased dermal microbiomes may ultimately fast-track identifying influential microbes associated with diseases, and their function within them.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

Bacterial skin infections are caused by bacteria that rely on several proteins to be infectious and resist antibiotic treatment. These proteins are encoded in the genome, or DNA, of the bacteria.

The specific knockout of these genes by genome editing has been shown to inhibit pathogenic bacteria, but delivery of the complexes that perform these modifications is still a major challenge.

To overcome this hurdle, we propose to use the large protein-injecting bacteriophage (a virus that can infect a bacterium) to inject a genome editing complex into bacteria. We will investigate the structure of the bacteriophage, to better understand which parts we can modify. We will exchange the recognition target of the bacteriophage, so that it can specifically bind to a bacterium of choice.

Additionally, we will modify the large protein of the bacteriophage that it normally injects, and replace it with a genome-editing complex: this will allow the targeted destruction of the DNA fragments in the bacterium that encode a protein that allows it to survive antibiotic treatment.

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.