Unge Forskere (Young Scientists) 2019-2021

Grantee: Mikkel Bohm, ASTRA, Sorø

Amount: DKK 6,000,000

Grant category: Education and awareness grants

Year: 2019

Geography: Denmark

Science is a powerful tool to understand and change the world for the better. The national Centre for Learning in Science, Technology and Health in Denmark – Astra* – wants to strengthen and develop science learning to train a new generation of young people with strong science competencies. It is important for the future of Denmark and our role in a globalized world.

One of Astra*’s activities is Unge Forskere (Young Scientists) which is Denmark’s largest talent competition for children from Danish elementary schools and high schools within STEM (Science, Technology, Engineering, and Mathematics).

The Unge Forskere-competition contributes to both talent development through participation in the competition, and it strengthens the work with innovation, idea development and the natural science method in daily teaching. It is a program that focuses both on the most talented young people, and generally strengthens the natural science identity and general science education among children and young people in Denmark.

Unveiling AMBRA1 as a prognostic biomarker in in vivo pre-clinical models of cutaneous melanoma

Grantee: Daniela De Zio, Danish Cancer Society Research Center, Copenhagen

Amount: DKK 2,900,000

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

The survival rate of patients with advanced melanoma has improved in recent years due to the clinical application of immune checkpoint inhibitors, as well as kinase inhibitors in BRAF/RAS-mutated melanoma cases.

However, melanoma remains a fatal diagnosis as a consequence of emerging resistance mechanisms and the absence of reliable biomarkers that identify high-risk tumour subsets, therefore impacting the stratification of these subsets for novel adjuvant therapies.

In the search for novel oncosuppressors that are altered in melanoma, we have found a promising candidate in the protein called AMBRA1. AMBRA1 has a fundamental role in the positive regulation of autophagy – a process which can elicit both pro- and anti-tumorigenic roles. Additionally, AMBRA1 finely modulates other crucial oncogenic processes, such as cell proliferation, cell invasion, and cell death.

Our preliminary research in a mouse model of melanoma has proven Ambra1 to be a crucial oncosuppressor, whose expression has been found highly altered in a number of human melanoma cells. Thus, by applying melanoma cell and mouse models in combination with systems biology approaches and state-of-the-art technologies, we aim to decipher the response of Ambra1-deficient melanomas to the current therapies.

Moreover, we will investigate the role of Ambra1 in regulating lipid metabolism in melanoma, which has recently been shown to profoundly affect its progression. Additionally, our aim is to assess the prognostic relevance of AMBRA1 in human cohorts of melanoma patients and understand whether AMBRA1 expression correlates with disease progression and whether it influences treatment.

Outcomes from this project will pave the way for novel clinical insight into the prognosis and treatment of melanoma patients.

This project is co-supported by a Young Investigator award from the Melanoma Research Alliance (MRA) in the USA of 224,500 USD (https://www.curemelanoma.org/research/grants/).

Novel quorum sensing inhibitors for anti-virulence treatment of skin infections caused by pathogenic Gram-positive bacteria

Grantee: Professor Christian Adam Olsen, Department of Drug Design and Pharmacology, University of Copenhagen

Amount: DKK 2,110,500

Grant category: Research grants in open competition

Year: 2019

Geography: Denmark

Staphylococcal bacteria are the most common cause of skin and soft tissue infections (SSTI) and with the rise of methicillin-resistant Staphylococcus aureus (MRSA) minor infections can lead to severe medical conditions.

The increasing antibiotic resistance development demands the search for alternative medicines with differing profiles ranging from prophylactic treatment of small infections to combating life-threatening conditions.

In the present project, we aim to inhibit this quorum sensing through a novel concept and thereby develop pan-staphylococcal inhibitors that are capable of treating the virulence in skin infections without the use of antibiotics.

Targeting the virulence of a bacterial infection rather than the viability of the pathogen represents such an alternative, because it increases the chance of clearance through the human immune system and attenuates disease symptoms while minimizing the risk of emerging resistance.

The expression of virulence factors in Gram-positive bacteria, including staphylococci, is regulated through quorum sensing (QS), which is a mechanism that allows bacteria to change gene expression in response to cell density.

This cell-to-cell communication is mediated by the secretion and detection of molecules termed autoinducing peptides (AIPs).

Functional characterization of dermokine in epidermal differentiation

Grantee: Professor MSO Ulrich auf dem Keller, Department of Biotechnology and Biomedicine, Technical University of Denmark

Amount: DKK 2,603,579

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.

Exploiting the untapped potential of the dermis to provide novel insight into the function of the skin microbiome

Grantee: Assistant Professor Christopher James Barnes, PhD, Natural History Museum of Denmark, University of Copenhagen

Amount: DKK 2,388,289

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.

Towards the targeted phage-based nanodelivery of genome editing complexes to render pathogenic skin bacteria harmless

Grantee: Associate Professor Nicholas Taylor, Faculty of Health and Medical Sciences, University of Copenhagen

Amount: DKK 2,996,539

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.

Life with Neurofibromatosis type 1

Grantee: Jeanette Falck Winther, Professor, Consultant, MD, DMSc; Danish Cancer Society Research Center (DCRC)

Amount: DKK 3,996,784

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.

Long-term improvement of psoriasis patients’ adherence to topical drugs: Testing a patient-supporting intervention delivered by healthcare professionals

Grantee: Mathias Tiedemann Svendsen, PhD, Specialist in dermato-venereology; Odense University Hospital

Amount: DKK 2,200,000

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.

Single Cell Sequencing Instruments – Add-on grant for LEO Foundation Skin Immunology Research Center

Grantee: University of Copenhagen

Amount: DKK 15,296,667

Grant category: Strategic 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.

Defining the mode of action of hydrocortisone on stem cell fate decisions in the epidermis

Grantee: Kim Jensen, Professor, BRIC, University of Copenhagen

Amount: DKK 2,754,990

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.