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:
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.
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.
The Science Olympiads (Science Olympiaderne)
Grantee: Niels Hartling, Science Olympiaderne
Amount: DKK 1,800,000
Grant category: Education and Awareness Grants
Year: 2023
Geography: Denmark
The Science Olympiads aim to stimulate the interest of Danish high school students in the fields of chemistry, physics, mathematics, biology, geography, and computer science. The Olympiad builds on six tracks – one in each of the six fields – which each follow the same structure, kicked off with annual nationwide competitions. Around 20,000 students participate in the national competitions, often as an integrated part of their high school education. The most talented students can qualify to participate in the international Science Olympiads. The Science Olympiads challenge gifted students to expand their talent, promote future careers in science, and provide them with a valuable network of peers
Influence of dietary derived gut microbial metabolites on skin barrier and atopic dermatitis development in early life (Infant AD)
Grantee: Clarissa Schwab, Associate Professor, Aarhus University
Amount: DKK 3,910,741
Grant category: Research Grants in open competition
Year: 2023
Geography: Denmark
Clarissa Schwab’s project aims to investigate the role of switching from liquid to solid diet in the development of AD during infancy.
Atopic dermatitis (AD) is one of the first manifestations of allergic diseases that occur in early life. In industrial countries, up to 30% of children suffer from AD imposing an enormous burden to the quality of life and to health systems.
Not all factors contributing to the occurrence of AD are known, but the development of the gut microbiota in relation to a switch from liquid to solid diet during the first year of life might play an important role.
This project, ‘Infant AD’, suggests that a combination of specific food components and the appearance of certain gut bacteria is critical to producing gut metabolites that affect the immune system, and ultimately the state of the skin. To tackle such a complex system at the interface of diet, microbiome and the host, the concept of Infant AD is based on a unique combination of microbial and/or nutritional intervention studies using in vitro and in vivo models with state-of-the-art microbiome and metabolome analysis that will be supported by data collected from the Swiss birth cohort Childhood, Allergy, Nutrition and Environment (CARE).
Infant AD may shed further light on the complex interactions between diet, microbial activity and the immune system that could lead to novel measures to lower the risk of AD development in infancy.