Dissecting the role of the ageing tissue microenvironment in inflammatory immune responses within human skin

Grantee: John Connelly, Professor, Queen Mary University of London, UK

Amount: DKK 3,501,669

Grant category: Research Grants

Year: 2025

Geography: United Kingdom

The normal healthy functions of our skin significantly decline with age, and these changes increase the risk of infection, chronic wounds, inflammatory diseases, and cancer. Therefore, understanding the biological mechanisms underlying skin ageing is essential to protect against age-related diseases and maintain healthy skin function. The aim of this project is to dissect the cellular, biochemical, and mechanical processes of skin ageing and to directly test how they impact key functions, including tissue homeostasis and immunity. We will take advantage of state-of-the-art imaging and genomic methods available within our institution to profile the ageing process, and advanced 3D culture models of human skin will be used to test key genes and biochemical pathways. The results will provide fundamental insights into human skin ageing, and over the long term, they have the potential to identify key therapeutic targets for counteracting or preventing age-related skin diseases.

Breaking the Cytokine Dogma: Integrin Signals from Langerhans Cells Drive Antibody Immunity in Skin

Grantee: Botond Igyártó, Associate Professor, Thomas Jefferson University, USA

Amount: DKK 4,192,650

Grant category: Research Grants

Year: 2025

Geography: USA

Most vaccines and textbook models assume that special immune messengers called cytokines (such as IL‑6 or interferon‑α) are needed to tell T cells what to become. These cytokines are normally triggered by adjuvants in vaccines or by the immune system sensing pathogens. Our new findings overturn this view. We discovered that Langerhans cells—immune sentinels in the skin—can trigger strong antibody responses even in the steady state, when those cytokines are absent. Instead of relying on inflammatory messengers, they use surface “grip” proteins (integrins) to fine‑tune the conversation with T cells. This cytokine‑independent pathway may explain how the immune system quietly learns from the skin microbiome and maintains balance, while errors in this mechanism could underlie autoantibody diseases such as pemphigus or lupus. Our first goal is to confirm these findings. Once established, they will guide new strategies for vaccines or treatments that prevent chronic inflammatory skin disease.

A pigmented view of ciliopathies

Grantee: Michael Marks, Professor, The Children's Hospital of Philadelphia, USA

Amount: DKK 3,989,364

Grant category: Research Grants

Year: 2025

Geography: USA

Human skin pigmentation is highly variable among world populations and determines skin sensitivity to ultraviolet radiation, susceptibility to skin cancer, vitamin D production, and other outcomes. Much of this variability is determined by genetics. Using genetic analyses among diverse native Africans, we and our collaborators linked skin pigment variation with levels of expression of a gene called TMEM138. Inactivating mutations in TMEM138 or about 200 other genes cause developmental disorders called ciliopathies in which the primary cilium – a cell structure not known to impact pigmentation – fails to form properly. This proposal seeks to use cultured skin pigment cells called melanocytes and reconstituted human skin to better understand the molecular mechanisms by which TMEM138 specifically, and the primary cilium more generally, regulates pigment formation. Our study will provide new insights into skin pigment physiology and diseases and into how ciliopathy classes differ.

Establishing the First Human Skin Organoid Platform to Redefine Therapies for CYLD Cutaneous Syndrome

Grantee: Abbas Shafiee, Senior Research Fellow, The University of Queensland, Australia

Amount: DKK 3,991,497

Grant category: Research Grants

Year: 2025

Geography: Australia

Skin diseases affect millions worldwide, yet research and treatment often rely on animal models that do not fully capture human biology. In this project, we will use patient-derived stem cells to grow miniature 3D models of human skin, called organoids. These living models mimic how skin develops, functions, and responds to disease, allowing us to study rare genetic conditions directly in the lab. By comparing patient organoids with genetically corrected “healthy” controls, we will uncover the biological mistakes that cause disease and identify new treatment targets. We will also test whether these organoids can predict how patients respond to therapies, offering a path toward safer and more effective medicines. This research aims to set a new standard for dermatology by reducing reliance on animal experiments, accelerating drug discovery, and improving care for people living with severe skin disorders.

Decoding microbial-immune crosstalk to modulate immune checkpoint inhibitor-induced skin toxicity

Grantee: Lisa Zaba, Associate Professor, Stanford University, USA

Amount: DKK 3,999,978

Grant category: Research Grants

Year: 2025

Geography: USA

Immunotherapy has transformed cancer treatment, helping the body’s immune system attack tumors. Unfortunately, these powerful drugs often cause side effects when the immune system also attacks healthy tissues. The skin is one of the most commonly affected organs, leading to rashes and other painful conditions that can force patients to stop life-saving therapy. Our project aims to understand why this happens. We recently discovered that certain immune cells, called CD8 T cells, are activated by bacteria living on the skin and then attack healthy skin cells during treatment. We will study how these bacteria and immune cells interact and test new ways to prevent this process. By uncovering how microbes trigger skin damage, our research could pave the way for safer cancer immunotherapies, helping patients stay on treatment longer while avoiding harmful side effects.

Mitochondrial transfer in wound healing

Grantee: Sabine Werner, Professor, ETH Zürich, Switzerland

Amount: DKK 3,560,550

Grant category: Research Grants

Year: 2025

Geography: Switzerland

Chronic wounds or hypertrophic scars affect a large percentage of the population world-wide, but the therapeutic options are still limited. The development of innovative wound therapeutics requires a thorough understanding of the mechanisms underlying normal and impaired healing. This project will study a new regulatory mechanism in wound healing – the transfer of metabolically highly active cell organelles (mitochondria) between different cell types and the functional consequences for wound healing. We will use state-of-the art cell culture and mouse models to determine if mitochondrial transfer has beneficial effects on recipient cells and if this promotes the wound healing process. Through collaboration with clinical partners, we will determine the importance of our findings for normal and impaired healing in humans. The results will pave the way for the development of new wound therapeutics that target mitochondrial transfer or proteins regulated by this process.

Developing Bioluminescent Madurella mycetomatis for Breakthrough Drug Discovery in a Novel Skin Model of Eumycetoma

Grantee: Wendy Laureijssen-van de Sande, Associate professor, ErasmusMC, Netherlands

Amount: DKK 3,999,996

Grant category: Research Grants

Year: 2025

Geography: Netherlands

Mycetoma is one of the world’s most neglected diseases – a slow growing skin infection that causes severe pain and deformities. It affects people in poor, rural areas across more than 20 countries, spanning five continents. The fungal form, eumycetoma, can lead to lifelong disability, and, in many cases, amputation. It is often accompanied by social stigma and mental health challenges, further isolating patients. Current treatments are toxic, unaffordable, and must be taken for up to a year – often with poor results. One major reason better treatments haven’t been developed is that there is no reliable way to test new drugs before trying them on humans. Wendy Laureijssen-van de Sande’s project will develop the first mouse model that closely mimics the human form of the disease. This will enable researchers to test new antifungal compounds more safely and effectively, laying the path for better, faster and more affordable treatments for patients who urgently need them.

Uncovering the cause of treatment resistance in autoimmune blistering disease

Grantee: Joanne Reed, Associate Professor, The University of Sydney, Australia

Amount: DKK 3,902,405

Grant category: Research Grants

Year: 2025

Geography: Australia

Autoimmune bullous disease is a condition where the patient’s immune system attacks their skin, causing painful blistering. Some patients develop blisters in the mouth, leading to difficulty eating and malnutrition or inflammation in the eye, which can cause blindness. There is no cure. Treatment involves suppressing the immune system but can lead to side effects and increased infections. Joanne Reed’s research will use new technology to investigate patient blood and skin samples left over from biopsies performed for diagnosis. The technology enables patient samples to be evaluated at an unprecedented level of detail to identify and study the immune cells and genes responsible for disease. This information will be used to develop a test that can predict patients at risk of severe symptoms to enable early intervention before permanent organ damage occurs. The detailed analysis of the disease-causing cells will also inform the development of new drugs that can specifically target these cells.

Exploring neutrophil metabolism as a therapeutic target in pyoderma gangrenosum

Grantee: Samreen Jatana, Staff Research Associate, Cleveland Clinic, United States

Amount: DKK 2,717,547

Grant category: Research Grants

Year: 2025

Geography: USA

Pyoderma gangrenosum (PG) is a rare skin disease. Patients with PG have defects in their skin wound healing responses. Even minor injuries and cuts to the skin can form large chronic ulcers. PG ulcers are enriched with neutrophils, an immune cell type that plays a vital role in skin wound healing. Typically, neutrophils travel to the skin right after an injury, perform their tasks, and leave within a period of 3 days. Samreen Jatana wants to understand why PG neutrophils don’t perform their regular tasks and impair wound healing in skin. Samreen Jatana and her colleagues analyzed peripheral blood from patients with PG and identified a type of neutrophil in circulation with features of immature neutrophils that typically live in the bone marrow. They anticipate that this neutrophil subset cannot utilize energy properly and might be exhausted to perform its function. In this project, they will study this neutrophil subset to understand if it can be targeted therapeutically to treat PG.

Immune Dynamics in Keloid-Prone Skin: Mechanisms of Inflammation and Fibrosis

Grantee: George Agak, Associate Professor, The Regents of the University of California, Los Angeles, United States

Amount: DKK 3,998,784

Grant category: Research Grants

Year: 2025

Geography: USA

Keloids are raised, inflamed scars that grow beyond the original wound, often becoming painful and disfiguring. They disproportionately affect African American, Hispanic/Latino, and Asian individuals, yet the biological reasons behind their formation remain unclear. Current treatments are limited, with high recurrence rates. George Agak’s research aims to uncover the molecular drivers of keloids by studying skin cells from keloid-prone individuals at the single-cell level. George Agak and his team focus on a key signaling pathway, the ACE-ASPN axis, which appears to promote inflammation and excessive scar formation. By using cutting-edge technologies like scRNA-seq, spatial-seq and advanced machine-learning tools, they will map how keloids develop across diverse skin types. Additionally, they will test whether angiotensin receptor blockers (ARBs)—drugs already used for high blood pressure—can reduce keloid growth. The goal is to identify targeted treatments, leading to personalized therapies for those most affected.