Exploring the serendipitous connection between a mitochondria fission protein and melanosomes maturation

Grantee: Marta Giacomello, Associate Professor, University of Padua

Amount: DKK 3,885,368

Grant category: Serendipity Grants

Year: 2023

Geography: Italy

Marta Giacomello aims to elucidate the role of a newly discovered mitochondrial fission protein in organelle maturation by exploring its impact on melanosome development and lipid droplet formation.

Melanogenesis, the process of synthesis and storage of the pigment responsible for skin color, melanin, occurs at specialized cell organelles named melanosomes. The mechanisms underlying melanin synthesis are not fully understood, but recent data suggest that mitochondrial physiology influences melanogenesis. Marta Giacomello and her team discovered that a mitochondrial fission factor, serendipitously found at the melanosome-mitochondria interface, controls the size of early melanosomes and melanin levels independently of its role in mitochondrial morphology.

The team aims to demonstrate that the identified mitochondria fission factor is a common regulator of organelle maturation, which exerts its specific effect based on its subcellular localization and interaction partners. They will first investigate its role in melanosome maturation, and then to generalize its function by extending the analysis to lipid droplets.

By elucidating how the identified fission factor switches from its mitochondrial to its melanosomal function, Marta Giacomello may generate milestone findings in the field of melanogenesis, and proof-of-concept evidence for its general role as a master regulator of organelles’ fission and maturation. Potentially, the results of this project could lead to breakthroughs in the fundamental understanding of cell biology.

An unexpected link between age-associated B cells and CD8 T cells

Grantee: Søren Degn, Associate Professor, Aarhus University

Amount: DKK 3,337,538

Grant category: Serendipity Grants

Year: 2023

Geography: Denmark

Søren Degn will investigate a novel link between age-related B cells (ABCs) and cytotoxic CD8+ T cells.

Søren Degn and his team have discovered a new and unexpected link between a type of immune cells that normally produce antibodies (B cells) and a type of immune cells that are responsible for eliminating the body’s own cells when they are infected or become cancerous (CD8+ T cells). Their preliminary findings indicate that this link may play an important role when the immune system is erroneously activated, when an infection cannot be cleared, or when a cancer is established. It is not known which exact signals are responsible for the communication between these two cell types, and whether it occurs directly or via a third-party messenger. However, it is known that it occurs in the spleen, an important immune organ, which filters the blood and prevents infections, but also plays a critical role in autoimmune diseases.

The intention of Søren Degn is to understand the cellular and molecular mechanisms behind this novel link. An increased understanding may enable new therapeutic strategies in the future across a range of important diseases such as inflammatory skin disorders, autoimmune diseases, and cancer.

Dr Abildgaard Fellowship 2023

Grantee: Dr. Terkild Brink Buus, Assistant Professor, University of Copenhagen, LEO Foundation Skin Immunology Research Center

Amount: DKK 12,000,000

Grant category: LEO Foundation Dr Abildgaard Fellowships

Year: 2023

Geography: Denmark

Project title: Staphylococcus aureus drives inflammation and disease activity in atopic dermatitis – novel approaches to old problems 

Fellowship theme: Skin Immunology and Inflammatory Skin Diseases

 

Terkild Brink Buus’ vision is to develop better strategies to manage Atopic Dermatitis (AD) and improve patient lives by increasing our understanding and providing vital insights into the underlying biology. AD is a debilitating disease affecting more than 30% of Danish children at great cost to patients, parents, and society.

Terkild Brink Buus’s project addresses the role of bacteria and their toxins in causing severe worsening of the AD. Building on his expertise in complex data analysis and research on aberrant T cells and skin inflammation, Terkild Brink Buus will explore how T cells – a vital part of our immune system – are hijacked by bacterial toxins to aggravate AD and how this can be counteracted by novel treatments.

Terkild Brink Buus hopes to increase our understanding of how bacteria and their toxins affect the skin and worsen the symptoms of AD patients. His research will provide the basis for initiating clinical trials of new treatment approaches targeting bacteria in AD patients as well as guidelines for how to determine which patients are most likely to benefit. Finally, he will provide several novel laboratory and analytical techniques that will be of high value to future research within inflammatory skin diseases.

Dr Abildgaard Fellowship 2023

Grantee: Dr. Stine Rønholt, Assistant Professor, University of Copenhagen, LEO Foundation Center for Cutaneous Drug Delivery

Amount: DKK 12,000,000

Grant category: LEO Foundation Dr Abildgaard Fellowships

Year: 2023

Geography: Denmark

Project title – ILnext: Unravelling the potential of ionic liquids as next generation cutaneous drug delivery systems

Fellowship theme: Skin Physiology and Cutaneous Drug Delivery

 

Stine Rønholt’s vision is to explore new ways to treat chronic skin issues (like eczema) directly on the skin. Today, such diseases are primarily treated by immunosuppressants, that upon systemic exposure can weaken the immune system. Atopic dermatitis is effectively treated by a type of medicine called JAK inhibitors, administered as tablets. Yet, direct administration of JAK inhibitors via the skin is hampered by the skin’s tough outer layer.

Stine Rønholt’s project will develop a new technology that treats eczema directly on the skin. To do so, Stine Rønholt is using a novel approach, “ionic liquids,” which can increase the drug solubility allowing for high dose treatment. Much like how sugar dissolves in water. This approach will help to deliver more medicine into the skin, targeting and treating eczema more effectively. Stine Rønholt’s goal is to figure out how to make this work for two specific JAK inhibitors, baricitinib and abrocitinib. Focus here is currently directed towards understanding how the ionic liquids used work together with the drugs, as well as what happens to the skin when the drug is applied. Even though the drug needs to be transported across the skin to where it is going to work, the technology should not cause any irritability to the skin. Special biophysical techniques are to be used to study all these things closely.

Stine Rønholt hopes to be able to deliver a high amount of medicine directly to a problem area without any uncomfortable procedures by using this approach. This could enhance treatment and lower the frequency of medicine required. Additionally, insights gained from Stine Rønholt’s project may pave the way for a new and improved method of addressing skin issues in a more efficient manner.

Dr Abildgaard Fellowship 2023

Grantee: Dr. Aida Hansen, Assistant Professor, University of Southern Denmark, Department of Molecular Medicine

Amount: DKK 12,000,000

Grant category: LEO Foundation Dr Abildgaard Fellowships

Year: 2023

Geography: Denmark

Project title – T-cell derived extracellular vesicles constitute pro-inflammatory packages that drive disease progression in psoriasis

Fellowship theme: Skin Immunology and Inflammatory Skin Diseases

 

Aida Hansen’s vision is to improve the treatment options for psoriasis patients by contributing to a more detailed understanding of the cellular cross-talk mediating the inflammatory processes in the disease. She aims to investigate a novel concept for cellular cross-talk, mediated by vesicular structures known as extracellular vesicles (EVs), that may drive inflammation in psoriasis.

Aida Hansen’s project builds upon knowledge that psoriasis is mainly driven by pro-inflammatory cytokines, and recently, it was discovered that cytokines are partly packaged into EVs. She hypothesizes that the majority of cytokines implicated in psoriasis are carried in specific subsets of EVs constituting “pro-inflammatory packages”. She will: 1) Do an in-depth investigation of the packaging of cytokines into EVs derived from patients with severe psoriasis, 2) Investigate the functional impact of specific EV-subpopulations in driving the inflammatory response in psoriasis, and 3) Explore the therapeutic concept for neutralizing specific disease-promoting EVs in psoriasis.

Aida Hansen hopes to contribute to a deeper understanding of how cytokines are being transported between cells and the potentially different biological properties of soluble cytokines compared to cytokines packaged into EVs. This is still poorly understood. The outcome of her project may lead to identification of new inflammatory pathways and novel depletion strategies for innovative therapeutic interventions to alleviate symptoms and improve the quality of life for patients with severe psoriasis.

Treatment of psoriasis during pregnancy, an immunological puzzle and a delicate balance

Grantee: Renate van der Molen, Assistant Professor, Radboud University Medical Center

Amount: DKK 2,596,390

Grant category: Research Grants in open competition

Year: 2023

Geography: Netherlands

Renate van der Molen’s project will study the effect of psoriasis and the associated treatment with biologics on the pre-pregnancy uterine immune environment and also investigate the effect on trophoblast invasion using a co-culture cellular model.

Pregnancy in patients with immune-mediated diseases like psoriasis is challenging and requires a tightly regulated immune system. The mother’s immune system must prevent rejection of the fetus that partly represents paternal characteristics and thus foreign to the mother’s immune system, while still being alert to infections threatening herself and the baby. Additionally, the immune system is important for invasion of fetal cells (trophoblast cells), into the cell lining of the womb to form a healthy placenta. Thus, a dysregulated immune system, i.e., during flares of psoriasis, can negatively affect pregnancy.

Furthermore, knowledge of the effect of biologics to treat psoriasis, anti-TNFα, anti-interleukin-17 (IL17) and anti-IL23, on pregnancy is sparse. This complicates decision making on treatment of women with psoriasis before and during pregnancy.

In this project, Renate van der Molen and her team will therefore study the effect of psoriasis and the treatment with biologics on the local uterine immune environment. In addition, using an innovative in vitro co-culture model of trophoblasts and immune cells they will study the effect of psoriasis and the treatment with anti-TNFα, anti-IL17 or anti-IL23 on trophoblast invasion.

Renate van der Molen’s project will give insights to whether and how psoriasis and the treatment with biologics can affect a future pregnancy, which is a step towards better evidence based clinical decisions on the best treatment for women with psoriasis with a child wish.

Investigate the onset of pathological remodeling events in SSc and assess their contribution to disease pathogenesis

Grantee: Valentina Greco, Professor, Yale University

Amount: DKK 3,818,950

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Valentina Greco’s project investigates the potential role of fibroblast and blood vessel maturation processes in systemic sclerosis (SSc) by monitoring development longitudinally in-vivo.

The skin protects organisms from their environment; it prevents water loss and infection and blocks physical insults. This barrier includes an outer layer and an inner, highly organized scaffold of fibers and blood vessels. Proper development of these two networks following birth is essential for health during adulthood; however, these processes are poorly understood.

Defects in the assembly and function of dermal fiber and blood vessel networks lead to severe diseases such as Systemic Sclerosis (SSc) or scleroderma. Identification of early SSc stages is crucial for the development of diagnostic, preventive, and therapeutic strategies. However, gaining this knowledge has been challenged by the inability to track these events longitudinally and in vivo.

Valentina Greco’s lab has overcome this roadblock and developed the ability for continuous visualization of skin networks, specifically how fibroblast and blood vessel networks develop after birth under healthy conditions. In this project – and building on this knowledge – they will utilize mouse models that mimic SSc in humans to investigate whether mechanisms crucial for postnatal skin maturation participate in this disease.

Valentina Greco’s project, if successful, will advance the understanding of the skin’s structural and blood vessel networks, shed light on their role in health and disease, and provide a solid foundation to improve clinical management of those suffering from often-lethal ailments such as scleroderma.

Modeling Hailey-Hailey disease to delineate its pathogenesis and identify therapeutic strategies

Grantee: Cory Simpson, Assistant Professor, University of Washington

Amount: DKK 4,054,629

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Cory Simpson’s project aims to investigate how mutations in the gene encoding the calcium pump SPCA1 cause the skin blistering disease Hailey-Hailey Disease (HHD) using human cellular and tissue models.

The epidermis forms the body’s outer armor from multiple layers of cells called keratinocytes, which assemble strong connections (desmosomes) to seal the skin tissue and prevent wounds. Several rare blistering disorders are linked to autoantibodies or gene mutations that disrupt desmosomes, causing keratinocyte splitting and skin breakdown. While autoimmune blistering diseases can be controlled by suppressing the immune system, treatments remain elusive for inherited blistering diseases.

One of these is Hailey-Hailey disease (HHD), which causes recurrent wounds, pain, and infections, leading to stigmatization of patients. Mutations in the ATP2C1 gene, which encodes the calcium pump SPCA1, were linked to HHD more than 20 years ago, yet the disease still lacks any approved therapies.

While it is known that SPCA1 resides in the Golgi apparatus (an organelle inside the cell responsible for protein processing and trafficking), our limited understanding of how SPCA1 deficiency compromises skin integrity has stalled drug development for HHD; moreover, mice engineered to lack SPCA1 did not replicate HHD.

Cory Simpson and his team at the University of Washington have built human cellular and tissue models of HHD to define what drives the disease and to discover new treatments. Their preliminary analysis of ATP2C1 mutant keratinocytes revealed impaired expression and trafficking of adhesive proteins, but also identified stress signals from mis-folded proteins and reactive oxygen species.

In this project, Cory Simpson and team will determine how these cellular dysfunctions compromise keratinocyte cohesion to cause skin blistering and test if cell stress pathways could serve as therapeutic targets for HHD.

Scarless wound healing: exploiting the regenerative properties of the spiny mouse

Grantee: Sofia Ferreira Gonzalez, Fellow, University of Edinburgh

Amount: DKK 3,995,846

Grant category: Research Grants in open competition

Year: 2023

Geography: United Kingdom

Sofia Ferreira Gonzalez’s project aims to characterize the regenerative capacity of the spiny mouse – the only mammal known to fully regenerate skin with minimal scarring – to optimize future wound treatment in humans.

Skin fibrosis is often a sequela of suboptimal wound healing following significant epidermal and/or dermal injury (burns, trauma, major surgeries). Fibrotic material replaces native skin with dense, non-functional connective tissue, ultimately leading to loss of function. In its mildest form, fibrosis is a minor aesthetic problem, but in the most severe cases it can lead to debilitating skin pathologies that result in limited movement, high morbidity, and prevention of patient reintegration into society.

Current treatments for fibrosis include physical therapy and surgery, but there are no therapies that directly target the underlying cellular and molecular mechanisms of skin fibrosis.

The spiny mouse (Acomys) is, to date, the only mammal capable of skin autotomy (i.e., self-amputation of the skin to elude a predator’s grasp). Fascinatingly, the spiny mouse completely regenerates the lost skin and regrows cartilage and appendages (nails, hair) with minimal fibrotic response.

A multimodal approach addressing the mechanisms driving spiny’s scarless regeneration may provide novel therapeutic opportunities to treat and prevent skin fibrosis.

In this project, Sofia Ferreira Gonzalez and her team investigate three questions: 1) is the spiny mouse’s scarless regeneration depending on specific cell populations, circulatory factors or a combination thereof, 2) which specific pathways are responsible for the scarless regeneration, and 3) how can the research findings be translated into novel therapeutics to improve skin wound healing in humans?

Skin barrier immune defence against the multidrug-resistant fungal pathogen Candida auris

Grantee: Adelheid Elbe-Bürger, Associate Professor, Medical University of Vienna

Amount: DKK 3,139,984

Grant category: Research Grants in open competition

Year: 2023

Geography: Austria

Adelheid Elbe-Bürger’s project investigates the pathogen:host interplay using ex-vivo skin models in relation to infections by Candida auris – a multidrug resistant fungus.

Drug-resistant microorganisms represent a serious human health threat worldwide. Candida auris (C. auris) is an emerging, multidrug-resistant human fungal pathogen. Its pronounced skin tropism (i.e., ability to infect) promotes persistent colonization of the skin and facilitates skin-skin transmission within health care facilities, leading to life-threatening infections of high mortality in immunocompromised patients.

The lack of clinically relevant primary human skin models with a disrupted barrier function has been a serious impediment to better understand the C. auris:host interplay during pathogenesis.

To counter this, Adelheid Elbe-Bürger and her team have developed unique, standardized human ex vivo skin models that allow them to study C. auris colonization and penetration as well as identify the immune cells that orchestrate both the recognition and immune defense against this fungus.

In Adelheid Elbe-Bürger’s project infected skin biopsies will be analyzed by single-cell RNA-sequencing, flow cytometry as well as confocal microscopy. Culture supernatants will be subjected to multiplex proteomics (i.e., a way to analyze many proteins simultaneously) to decipher host components governing fungal:host interactions.

The overarching aim is that the results will advance the understanding of tissue-specific mechanisms of anti-C. auris defense and may help to pave the way for improved therapeutic options.