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Grant category: Standalone grants

Year: 2023

Geography: Denmark

The Costerton Biofilm Center (CBC) at Department of Immunology and Microbiology (ISIM), University of Copenhagen, is a world-leading interdisciplinary research center dedicated to exploring chronic infections caused by bacteria, including skin infections. The center runs two infrastructure facilities which are open to external users from basic, clinical, and industrial research. 

There is an urgent need in the center’s Biofilm Test Facility to replace an outdated confocal laser scanning microscope which can no longer be serviced. The grant from the LEO Foundation therefore hopes to provide this upgrade, the microscope a critical tool in the CBC’s pioneering work on understanding how the ability of bacteria to form biofilm is key to addressing antimicrobial resistance and developing novel antibacterial treatments.  

Grant category: Research Grants in open competition

Year: 2023

Geography: Denmark

This project of Ulrich auf dem Keller aims to elucidate the potential role of a set of recently discovered proteins in atopic dermatitis that may contribute to disease development.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects people of all ages. It is one of the most common skin diseases, affecting approximately 10-20% of children and 1-3% of adults worldwide. AD can be a frustrating and uncomfortable condition that can significantly impact a person’s quality of life.

Despite extensive research it is not fully clear, if AD is primarily caused by a defect barrier function of the skin, allowing uncontrolled entry of environmental allergens that trigger an immune response, or by immunological disorders that in turn weaken the skin’s protective barrier, exaggerating the disease in a vicious cycle. Most likely, both contribute to predisposition and development of AD, but there are differences between patients which call for customized therapies.

Together with basic skin researchers in Switzerland and dermatologists in Germany, Ulrich auf dem Keller has identified proteins in non-lesional skin of AD patients whose activities might impair skin barrier integrity mostly independent of an immune response. This project will use human skin models and advanced protein analytics to understand if and how they might exert these detrimental activities and thereby contribute to predisposition to AD in affected individuals. Moreover, they will test their findings in samples from AD patients with a long-term aim to contribute to new strategies for development of therapeutics as alternatives to frequently applied emollients in barrier repair therapy.

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.

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.

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Rasmus Hartmann-Petersen’s project aims to characterize all possible missense variants (changes in genes which introduce a different amino acid in the resulting protein) in human keratins and investigate the importance of these variants in associated diseases.

Keratins are intermediate filament proteins that form a cytoskeletal network within cells. They are expressed in a tissue-specific fashion and form heterodimers, which then further oligomerize into filaments. Variants in several keratin encoding genes are linked to a range of hereditary disorders, including several epidermal skin diseases. On the molecular level, some pathogenic keratin variants appear to cause aggregation of the keratins.

In Rasmus Hartmann-Petersen’s project it is hypothesized that most keratin-disorders are protein misfolding diseases, i.e. diseases where the underlying genetic variants cause misfolding of the encoding protein. Rasmus and his team aim to explore this hypothesis by using computational tools, including large language models (a specific form of AI). They will test the validity of the computational predictions through focused cellular studies on selected keratins and identify components regulating keratin turnover.

The results will highlight the underlying molecular mechanisms for keratin-linked human disorders and provide predictions on the severity of all possible (both known and yet unobserved) coding variants in human keratin genes. The results could be of diagnostic value, but may also highlight the cellular protein folding and protein quality control machinery as potential therapeutic targets.

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Brian Capell’s project seeks to better understand how epigenetic changes (modifications that do not change the sequence of genomic DNA) regulate the development of sebaceous glands.

Dysfunction of sebaceous glands (SGs) has been linked to a variety of common skin disorders ranging from atopic dermatitis to acne, sebaceous hyperplasia, seborrheic dermatitis and sebaceous tumors.

Brian Capell and his team have recently discovered that through genetic modification of the epigenome, they could promote a dramatic increase in the number and size of SGs (Ko, et al. Developmental Cell. In press. 2024). This surprising result demonstrated the direct role that epigenetics and chromatin organization plays in controlling SG development and abundance. It also suggested that targeting the epigenome might offer new ways to treat disorders characterized by aberrant SG development and activity.

Diseases related to aberrant SG development or activity can have a deleterious effect on both human physical and mental health. Despite this, very little is known of the role of epigenetics in SG development and homeostasis. To address this, Brian Capell’s project aims to test the influence of epigenomic modifiers and modifications upon SG development and disease to further dissect their contribution to the pathogenesis of these very common conditions.

Collectively, this project will address outstanding questions regarding the role of the epigenome in SG development and homeostasis and in common diseases driven by SG dysfunction – diseases that are both understudied and in need of better therapies.

Grant category: Research Grants in open competition

Year: 2024

Geography: Austria

Georg Stary’s project aims to investigate interactions between T cells and structural cells, including keratinocytes, in the skin and how this cellular communication may affect the function of the T cells in dermatological diseases.

Human skin is protected by specialized T cells, called tissue-resident memory T cells (TRMs), which are needed to protect against infection at the site of pathogen encounter, but can also mediate inflammation in certain conditions. The exact regulation of TRMs in human skin is not well understood, hence TRM-targeted therapies are currently unavailable.

Georg Stary and his team have discovered that T cells communicate with structural cells of the skin via certain surface molecules and acquire a TRM phenotype after interaction with keratinocytes and fibroblasts. Some of the newly described molecules that instruct T cells to become TRM have not been implicated in the regulation of T cell tissue residency before.

Georg and his team aim to explore how structural cells of the skin instruct the maintenance of human TRM, and how this cellular crosstalk changes during inflammation. Based on preliminary data, they will unravel the function of certain co-receptors in TRM regulation using modern single-cell sequencing technologies on primary tissue from patients and ex-vivo co-culture systems with genetically engineered human cells. Based on this, they will subsequently test the therapeutic potential of targeting T cell-structural cell interactions in a humanized mouse model of TRM-mediated skin inflammation.

This study will not only inform about new mechanisms of human TRM instruction in health and disease and explore options for developing clinical applications targeting interactions with structural cells, but also form the basis for designing clinical studies to treat selected TRM-mediated diseases, such as graft-versus-host disease or psoriasis.

Grant category: Research Grants in open competition

Year: 2024

Geography: France

Nicolas Manel’s project explores the mechanisms of skin aging and immunity dysfunction, with a focus on establishing a novel model for investigating the role of the nuclear envelope in skin aging.

Genome instability is considered a central mechanism of aging. The nuclear envelope is essential for genome stability. Nicolas Manel’s laboratory recently reported that in mice deficient for a protein of the nuclear envelope in the immune system, alveolar macrophages, but not other lung immune cells, acquire aging hallmarks and decline in number, as observed in chronological aging. This established that deficiency of a nuclear envelope component can represent a cell-intrinsic model of accelerated aging in specific immune cell types. In preliminary results, further explorations revealed that subsets of skin immune cells are also decreased in a mouse model of nuclear envelope deficiency. Interestingly, the same skin immune cells are decreased in the aged skin of humans and mice. Nicolas Manel’s project will test the hypothesis that loss of nuclear envelope integrity is a mechanism of aging in these skin immune cells. It aims to define the mechanisms leading to skin immune cell depletion, the impact on the immune cell homeostasis in the skin, and the pathophysiological consequences of such depletion in skin immunity against age-related pathologies.

The results of the project have the potential to reveal new fundamental pathways in the aging of skin immunity and its impact on the health of aged individuals.