Epidemiology and genetics of rosacea and co-morbidities
Grantee: Ole Pedersen, Chief physician , Professor, Zealand University Hospital, Køge
Amount: DKK 2,715,598
Grant category: Research Grants in open competition
Year: 2024
Geography: Denmark
Ole Pedersen’s project aims to determine the genetic basis of rosacea and the causal connection between rosacea and its comorbidities.
Rosacea is a common chronic inflammatory skin disease of the face, which may manifest as a bulbous nose, central erythema, flushing, inflammatory papules/pustules, or broken vessels in addition to diverse eye involvement. Severe rosacea has a large impact on the patients’ quality of life, social and psychological well-being and has been linked to many systemic comorbidities including cardiovascular, psychiatric, neurological, and cancer diseases.
Ole Pedersen’s project aims to identify the genetic pathways of rosacea and determine the causal connection and modifiable risk factors to previously reported systemic comorbidities. He has recently developed a rosacea classification tool and applied it to a deep phenotyped cohort of ~55,000 Danes allowing for detailed analysis of association between rosacea, risk factors and co-morbidities. In addition, Ole Pedersen has facilitated genotyping of 500,000 Danes that can be used for genome wide association study meta-analysis with other genetic cohorts from Iceland, Finland, UK and USA to perform the so far largest genetic study on rosacea. Based on this analysis, his project will determine the genetic correlations and perform Mendelian randomization analysis of the causation between rosacea and comorbidities.
Ole Pedersen’s project may provide new understanding of disease pathogenesis and the link to systemic comorbidities, paving the way for developing new treatments and early targeted interventions.
Development of novel RNA replicon vectors for treatment of skin genetic disorders
Grantee: Xiaoyang Wu, Associate Professor, University of Chicago
Amount: DKK 4,000,000
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Xiaoyang Wu’s project aims to engineer self-amplifying RNA vector as a platform for gene therapy of recessive X-linked ichthyosis, with potential for treatment of other skin diseases.
Skin ichthyoses are a group of heterogeneous genetic diseases that are characterized by hyperkeratosis, localized or generalized scaling, and often associated with xerosis, hypohidrosis, erythroderma, and recurrent infections. So far, mutations in more than 50 genes have been shown to cause ichthyosis, which affect a variety of different cellular processes, ranging from DNA repair, lipid biosynthesis, cell adhesion, and skin differentiation. Recessive X-linked ichthyosis (RXLI) is the second most common form of inherited ichthyosis. RXLI is caused by mutations in the STS gene on the X chromosome, which encodes microsomal steroid sulfatase. The skin abnormalities of RXLI are caused by the impact of excess cholesterol sulfate, which affects lipid synthesis, organization of the lamellar lipids that provides the skin permeability barrier, corneodesmosome proteolysis, and epidermal differentiation.
As a genetic disorder, RXLI is a life-long condition that can significantly affect domestic life and cause psychological problems for the patients. More effective treatment beyond current symptomatic management is urgently needed. Xiaoyang Wu’s project will explore the possibility that engineered self-amplifying RNA vector can serve as a novel platform for gene therapy of RXLI.
Xiaoyang Wu’s project may serve as proof-of-concept for a novel paradigm for the treatment of patients with genetic skin disorders.
Inhibitors of ERAP1 or ERAP2 to modulate antigen processing towards new psoriasis treatment
Grantee: Rebecca Deprez-Poulain, Professor, Institut Pasteur de Lille
Amount: DKK 3,190,714
Grant category: Research Grants in open competition
Year: 2024
Geography: France
The IL-18 Conundrum: Investigating the role of IL-18 the pathogenesis of atopic dermatitis
Grantee: Christoph Schlapbach, Associate Professor, Inselspital, Bern University Hospital, University of Bern
Amount: DKK 3,942,000
Grant category: Research Grants in open competition
Year: 2024
Geography: Switzerland
Christoph Schlapbach’s project aims to elucidate the role of interleukin (IL-)18 in atopic dermatitis (AD), a prevalent, chronic skin disease with significant burden and unmet therapeutic needs.
IL-18 is linked to AD pathogenesis by multiple lines of evidence: IL-18 receptor (IL-18R) gene variants associate with AD susceptibility, IL-18 levels correlate with disease severity, and animal models of AD suggest a pro-inflammatory function of IL-18 in type 2 skin inflammation. Yet, the functional link between IL-18, considered a Th1-promoting cytokine, and AD, a Th2-driven disease, remains obscure. Christoph Schlapbach’s preliminary data now indicate that (i) there is a functional link between AD-associated IL18R gene variants and heightened Th2-cell responses, (ii) IL-18 can promote secretion of pathogenic cytokines in Th2 cells of AD patients, and (iii) skin explants from lesional AD skin can be used to model the effects of IL-18 in the complex environment of human skin.
Christoph Sclapbach’s project will leverage genotype-phenotype-function studies in a translational approach to dissect the mechanisms by which IL-18 influences Th2 cell-mediated inflammation in AD. Utilizing state-of-the-art methodology and functional validation experiments, the study aims to clarify IL-18’s role in AD pathogenesis to answer this long-standing conundrum in the fields of dermatology and immunology.
The results of Christoph Schlapbach’s project may provide a new understanding of IL-18’s role in AD, potentially enabling improved treatment.
Control of Langerhans cell dynamics and function by the microtubule cytoskeleton
Grantee: Jeffrey Rasmussen, Assistant Professor, University of Washington
Amount: DKK 3,834,520
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Impact of ageing on epidermal cell fate plasticity
Grantee: Maria Alcolea, Associate Professor, University of Cambridge
Amount: DKK 3,887,952
Grant category: Research Grants in open competition
Year: 2024
Geography: United Kingdom
Boosting the phagocytic clearance of apoptotic cells for better wound healing during primary skin injury repair and upon secondary assaults
Grantee: Sophia Maschalidi, Assistant Professor, Universiteit Gent
Amount: DKK 3,986,871
Grant category: Research Grants in open competition
Year: 2024
Geography: Belgium
Harnessing Novel Partial Reprogramming Technology to Revitalize Aging Skin Fibroblasts for Enhanced Wound Healing
Grantee: Yossi Buganim, Associate Professor, The Hebrew University of Jerusalem
Amount: DKK 3,996,300
Grant category: Research Grants in open competition
Year: 2024
Geography: Israel
Yossi Buganim’s project investigates the mechanisms behind fibroblast dysfunction in aging skin and develops a novel technology for rejuvenating aged fibroblast to improve wound healing.
Fibroblasts are pivotal in orchestrating skin wound healing processes, contributing to fibrin clot breakdown, extracellular matrix synthesis, collagen formation, and wound contraction. These multifaceted roles highlight their significance in skin repair following injuries, which trigger a cascade of synchronized healing mechanisms. Despite their crucial functions, aging impairs fibroblast functionality, leading to prolonged and impaired wound healing processes, increasing susceptibility to chronic wounds and scarring. Elderly individuals experience delayed wound healing, partly attributed to reduced cell division of the aged fibroblasts and diminished fat cell production and attraction to the wound area, resulting in thinning skin and heightened vulnerability to injuries. Moreover, aging cells exhibit slower regeneration, compromised bacterial defense mechanisms, and increased inflammation, further hindering the healing process.
Addressing these age-related impairments is imperative for advancing wound care strategies. Yossi Bunganim’s project seeks to elucidate the molecular mechanisms underlying fibroblast dysfunction in aging and leverage novel partial reprogramming technology to rejuvenate aged fibroblasts, enhancing wound healing outcomes.
Yossi Bunganim’s project aims to develop innovative interventions to mitigate the burden of chronic wounds and scarring in the aging population, ultimately improving overall quality of life and healthcare outcomes.
A novel model to study aging of skin immunity
Grantee: Nicolas Manel, Research Director, Institute Curie
Amount: DKK 2,723,700
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.
Decoding circadian host-microbiome skin interactions in health and psoriasis
Grantee: Eran Elinav, Head of Department, Weizmann Institute of Science
Amount: DKK 4,000,000
Grant category: Research Grants in open competition
Year: 2024
Geography: Israel
Eran Elinav’s project explores the role of circadian rhythm in regulating host-microbiome interactions in the skin, and the impact of abnormal circadian rhythm on the microbiota of the gut, with a potential link to skin inflammation, psoriasis in particular.
While the exact cause of psoriasis remains elusive, it is believed to stem from a combination of genetic and environmental factors, including dietary and biological clock-related influences. The mechanism by which these factors impact psoriasis is closely tied to the circadian rhythm, as evidenced by the abnormal circadian rhythms observed in psoriasis patients. In recent years, the pivotal role of the microbiota – the trillions of indigenous microorganisms inhabiting the human body – has come to the forefront. Eran Elinav’s group has recently uncovered that circadian disruption can exacerbate inflammatory diseases by disrupting the diurnal oscillations of the gut microbiota. His project explores how the circadian clock may also orchestrate fluctuations in the dermal microbiome, which could be crucial in understanding skin diseases such as psoriasis.
Eran Elinav’s project aims to identify novel host-microbiome interactions in the skin and generate a novel framework for microbiome-based interventions for psoriasis.