NEMFU: Impact of neuromicrobiota in diabetic foot ulcers

Grantee: Friedrich Götz, Professor, University of Tübingen

Amount: DKK 2,530,167

Grant category: Research Grants in open competition

Year: 2023

Geography: Germany

Friedrich Götz’s project aims to elucidate the role of bacteria-derived neurotransmitters in the development and progression of diabetic foot ulcers (DFU) and DFU-associated peripheral neuropathy (DPN).

A diabetic foot ulcer (DFU) is a poorly healing open wound that occurs in about 15% of patients with diabetes. Of those who develop DFU, 6% will be hospitalized due to infection or other ulcer-related complications. Previously, Friedrich Götz and his team have found evidence that neurotransmitter-producing bacteria of the skin (here termed neuromicrobiota) may have an impact on the healing process. However, it remains unknown whether the effects are beneficial or detrimental to wound healing.

In Friedrich Götz’s project it is hypothesized that permanent stimulation of neuronal skin receptors is more detrimental for wound healing. Through a close collaboration with the Trauma Surgery at the University Tübingen, BG Clinic Tübingen which treats ~200 DFU patients/year, samples will be analyzed for a variety of parameters, including neurotransmitter content, microbiome and metagenome composition, and impact of neurochemicals on wound healing. These will be compared to samples from healthy subjects taken at similar sites.

The goal of the project is to elucidate the role of bacteria-derived neurotransmitters in the development and progression of DFU and DFU-associated peripheral neuropathy (DPN). Friedrich Götz’s project will substantially aid the scientific understanding of DFUs and may provide potential for clinical application. If bacterial-derived neurotransmitters are found to have an impact on wound healing and progression of DFU, then this may open a new avenue for therapeutic approaches to treat DFU.

Accelerating to Zero Transmission of Leprosy in Nepal (ACCELERATE)

Grantee: Sarah Dunstan, Principal Research Fellow, University of Melbourne

Amount: DKK 4,000,000

Grant category: Research Grants in open competition

Year: 2023

Geography: Australia

Sarah Dunstan’s project aims to whole-genome sequence the leprosy-causing bacteria (Mycobacterium leprae) found in specific areas of Nepal to understand disease epidemiology, transmission dynamics and persistence to improve treatment strategies.

Leprosy, a neglected tropical disease of the skin, causes severe stigmatization, long term disability and mental health issues. It is treatable and preventable yet persists among the world’s poorest and most neglected citizens. To realize the goal of a leprosy-free world we need to deepen the knowledge of the disease pathophysiology and how it spreads, and ensure effective strategies to diagnose, prevent, and cure the disease and its long-term effects. Major gaps exist in the understanding of leprosy transmission which limit the efficiency of interventions to prevent infections and achieve zero transmission.

Sarah Dunstan’s project will use whole genome sequencing of the causative agent, Mycobacterium leprae, to unravel the complexities of leprosy epidemiology and persistence. The knowledge gained will also improve interventions for diagnosis, treatment, and vaccine strategies, and develop a robust framework for obtaining the zero-transmission goal in Nepal. A network of community health workers will conduct active case finding for leprosy in the community in two districts of Nepal with a high incidence of leprosy and high multidimensional poverty index (i.e., poverty in relation to health, education and living standards). Genomic epidemiology will be used to characterize subtypes of the M. leprae identified, matched to individual patients, disease transmission dynamics and drug resistance emergence. Mathematical models will inform optimized active case finding, and this will form the basis of stakeholder engagement to develop evidence-informed policy revisions in the national strategic plan for leprosy.

Phage therapy to treat group A Streptococcus in Necrotizing Soft Tissue Infection

Grantee: Thomas Sicheritz-Pontén, Professor, University of Copenhagen

Amount: DKK 3,988,469

Grant category: Research Grants in open competition

Year: 2023

Geography: Denmark

The project led by Thomas Sicheritz-Pontén from the Globe Institute at the University of Copenhagen, aims to carry out the fundamental work needed to develop targeted phage therapy (using bacteria-infecting viruses) to counter Necrotizing Soft Tissue Infections (NSTI).  This innovative treatment approach necessitates an in-depth understanding of the causative organisms, which will be achieved through sequencing these organisms and employing machine learning algorithms to predict their susceptibility to specific phages.

Necrotizing Soft Tissue Infections (NSTI), also known as “flesh-eating disease”, are rapidly escalating globally, posing a deadly bacterial threat that necessitates innovative therapeutic strategies due to its profound impact on human health. NSTI is characterized by aggressive skin manifestations primarily caused by Group A Streptococcus (Strep A). Although prompt surgery and antibiotics serve as the first-line treatment, infections often progress to necrosis, rendering antibiotics ineffective and often necessitating amputation and in worst case death.

Bacteriophages, or simply phages, offer a promising avenue to address this severe skin and soft tissue infection. Phages are viruses that selectively infect and eliminate bacteria, including antibiotic-resistant strains, without harming human cells.

Thomas Sicheritz-Pontén and team will do the fundamental work needed to identify prototype tailored phage therapies targeting Strep A. Along with his team, comprised of chief physicians from three different Danish hospitals, the UK Centre for Phage Research and the University of Copenhagen, Thomas Sicheritz-Pontén intends to identify phages capable of rapidly eradicating the bacteria, harness bacterial enzymes (endolysins), and employ phage satellites (mobile genetic elements that parasitize phages) for gene delivery.

By collaborating across research hubs, the team will decode Strep A’s genetic makeup, thereby facilitating the creation of precise phage cocktails and develop a novel molecular typing system to predict bacterial susceptibility, streamlining targeted phage treatments.

If successful, Thomas Sicheritz-Pontén’s project may greatly aid the battle against deadly NSTI infections through innovative development of phage therapy.

Programming dermal fibroblasts to stimulate hair follicle regeneration

Grantee: Peggy Myung, Associate Professor, Yale University

Amount: DKK 2,135,432

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Peggy Myung’s project aims to elucidate how two key molecular signals regulate the development of dermal condensate cells, a group of cells pivotal for hair formation.

The hair follicle dermal condensate (DC) is a cluster of quiescent dermal cells that can induce new hair follicle formation and holds the potential to revolutionize hair loss treatments. However, a key barrier to exploiting DCs to make new hair is that the molecular and cellular mechanisms that lead to DC formation are poorly understood.

Peggy Myung and her team recently identified two morphogen signals that are necessary and sufficient to drive DC formation. These two signals cooperate to unfold an initial stage of progenitor proliferation followed by a stage of cell cycle exit and DC maturation. Importantly, these stages of differentiation depend on levels of these two signals: Low levels induce progenitor proliferation; higher levels induce quiescence and DC maturation.

They hypothesize that different signaling levels regulate these stages of differentiation by inducing distinct signature genes that cause either DC progenitor expansion or terminal differentiation. They recently established a high-throughput dermal culture system to test this hypothesis. Using this novel platform and in vivo hair reconstitution assays, they aim to define how modulation of levels of these two signals regulates dermal gene expression profiles, cell cycle dynamics and DC function.

If successful, Peggy Myung’s project may define tunable molecular targets to develop novel treatments for hair loss and to make DC organoids for drug testing.

The ribotoxic stress response in inflammatory skin disease

Grantee: Simon Bekker-Jensen, Professor, University of Copenhagen, Center for Healthy Aging

Amount: DKK 3,823,440

Grant category: Research Grants in open competition

Year: 2023

Geography: Denmark

Simon Bekker-Jensen’s project investigates the potential role of the NLRP1 (Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat and Pyrin Domain Containing 1) inflammasome in combination with the upstream activator Ribotoxic Stress Response (RSR) in AD and psoriasis.

Inflammatory and hyperproliferative skin diseases, including atopic dermatitis (AD) and psoriasis, are associated with cascades of inflammatory events. A key player in innate skin immunity is the NLRP1 inflammasome, which mediates inflammation and cell death in response to a wide array of stress insults. In human keratinocytes, NLRP1 was recently shown by Simon Bekker-Jensen’s team and others to be activated by the Ribotoxic Stress Response (RSR) upon exposure to UV-B irradiation and a range of bacterial toxins.

Based on their preliminary data demonstrating that the RSR also mediates inflammation and keratinocyte hyperproliferation in vivo, the team hypothesize that these pathways have broader implications for the pathogenesis of inflammatory skin diseases.

In Simon Bekker-Jensen’s project, the validity of the RSR as a therapeutic target in the common inflammatory skin diseases psoriasis and AD will be explored. By genetic deletion and pharmacological inhibition of the RSR, the team will interrogate this pathway in several mouse models of inflammatory skin diseases. In addition, they will generate a humanized NLRP1 mouse model to study the RSR-NLRP1 signaling axis in vivo. Finally, by using 3D organotypic skin models and skin biopsies from patients, they aim to firmly establish the role of the RSR in psoriasis and AD.

The long-term goal is to leverage this insight to develop new therapeutic options for the management and treatment of inflammatory skin diseases.

Unravelling the diversity and function of skin-resident T cells

Grantee: Laura Mackay, Professor, University of Melbourne

Amount: DKK 3,826,119

Grant category: Research Grants in open competition

Year: 2023

Geography: Australia

Laura Mackay’s project investigates how tissue-resident T cell (TRM) populations in skin vary in development and function across body surfaces exposed to different environmental factors.

The generation of optimal immunotherapies requires effective T cell responses. Whilst some T cells patrol the blood, a unique subset called tissue-resident memory T (TRM) cells permanently exist within the tissues of the body. T cells that reside in the skin comprise distinct populations that differentially contribute to protecting the skin against disease.

The previous work of Laura Mackay and her team has demonstrated that different populations of skin-resident T cells in mice rely on separate molecular processes to function effectively. However, understanding of how human skin-resident T cells develop and control infectious insults and inflammatory disorders remains limited.

This project aims to determine skin TRM cell variation across the body, encompassing skin sites exposed to different environmental factors, such as sun exposure and hair follicle density, as well as in the context of disease. The team will seek to define the molecules that enhance skin-resident T cell function and survival, thus identifying factors that may prevent disease in healthy skin.

Overall, the aim is to generate fundamental new knowledge about the regulation of skin immunity and homeostasis. This knowledge is critical for the development of treatments and immunotherapies to harness T cell immunity for skin disorders.

Global Atopic Dermatitis Atlas (GADA)

Grantee: Carsten Flohr, King's College London

Amount: DKK 10,000,000

Grant category: Standalone grants

Year: 2023

Geography: United Kingdom

Atopic dermatitis, also called atopic eczema, or just eczema, is a non-contagious, chronic skin disease, causing dry, patchy, and itchy skin. It affects up to 20% of children and up to 10% of adults. Of all skin diseases worldwide, it is the most common type, with a burden that remains a significant challenge for the people affected, their families, and societies.

Despite progress made in treating severe forms of atopic dermatitis, there is a need for high-quality information showing how many people per country have atopic dermatitis and how severe it is. With strong data, atopic dermatitis can be better understood and treated.

With a grant from the LEO Foundation, the Global Atopic Dermatitis Atlas, or GADA, will help address gaps in current data by creating and maintaining a living online atlas, where the newest research-based knowledge and data on atopic dermatitis, its prevalence, severity, and treatment are available in one place – collected and analyzed in the same way for all countries.

About GADA

The Global Atopic Dermatitis Atlas (GADA) is a worldwide, long-term project. GADA is led by Professor Carsten Flohr (St John’s Institute of Dermatology, King’s College London, UK) and is an initiative established by the International League of Dermatological Societies (ILDS) in 2022 in collaboration with supporting stakeholders:

Visit GADA’s website

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On track (På sporet – elever i 2. klasse lærer tal og algebra med læringsspor)

Grantee: Charlotte Skott, Professionshøjskolen Absalon

Amount: DKK 2,500,872

Grant category: Education and Awareness Grants

Year: 2023

Geography: Denmark

This project aims to apply a new research-based approach to enhance the teaching of mathematics in Denmark (called learning trajectories or Læringsspor in Danish), involving second-grade students and their mathematics teachers in all the public schools of Kalundborg as a first case. Learning trajectory constitutes an approach to numbers and algebra which has achieved promising results in international research. During the project, the Kalundborg mathematics teachers will learn about the approach and learning trajectories and be involved in developing educational material suited for a Danish context.

Science in reality (Videnskab i virkeligheden)

Grantee: Marie Erbs Ørbæk, CPH:DOX

Amount: DKK 980,000

Grant category: Education and Awareness Grants

Year: 2023

Geography: Denmark

CPH:DOX’s UNG:DOX program currently covers the greater Copenhagen area with a natural science educational focus during the two-week annual documentary film festival in March. Plans are underway to expand UNG:DOX to cover youth educations all over Denmark, providing year-round access. UNG:DOX offers upper secondary level students science documentaries from its international program, through streaming or live events, accompanied by expert lectures, scientist interviews, and additional resources for teachers.

Visit UNG:DOX’s webpage

Natural Science Marathon (Naturfagsmarathon)

Grantee: Maiken Lykke, Naturvidenskabernes Hus

Amount: DKK 2,000,000

Grant category: Education and Awareness Grants

Year: 2023

Geography: Denmark

This project continues the established ‘Naturfagsmaraton’ which provides a practice-oriented, engineering-inspired approach to STEM education with competitions revolving around real-world challenges, developed in collaboration with Danish companies. The project expands the current program aimed at 5th-6th grade pupils with an annual mini-marathon tailored for younger pupils.

Visit Natural Science Marathon’s webpage