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.

Repair Glia: An Overlooked Cell Type Orchestrating Skin Wound Healing

Grantee: Lukas Sommer, Professor, University of Zurich

Amount: DKK 3,781,580

Grant category: Research Grants in open competition

Year: 2024

Geography: Switzerland

Lukas Sommer’s project explores the mechanisms mediating the role of repair glia in skin wound healing by means of genetically engineered mouse models and an organotypic 3D culture system of human skin wounds.

Inefficient skin wound healing can cause severe medical problems, including chronic wounds and ulcers. Innervation is a critical player in tissue regeneration and repair. While most studies have linked this effect to signaling from axons, there is increasing evidence for peripheral glia contributing to successful wound healing. Lukas Sommer’s laboratory has recently shown that peripheral glia following skin injury to become repair glia, which promote the wound healing process by paracrine signaling. In his project, single cell RNA sequencing on the cellular microenvironment in presence or absence of repair glia at defined timepoints after skin injury will be performed and complemented with spatial omics approaches to characterize the gene expression profile of repair glia and to identify their mode of intercellular communications with other skin cell types. Multiplex optical imaging approaches on biopsies of murine and human skin lesions will allow the investigation of the relevance of our findings in human skin diseases. Finally, functional validation of key candidate factors in mice and in 3D reconstituted human skin wounds will determine how repair glia promote the wound healing process and which signaling pathways could potentially represent targets for treatment.

Lukas Sommer’s project therefore aims to enhance our understanding of wound healing mechanisms with potential broad applications in medicine.

ESDR Future Leaders Academy 2024

Grantee: European Society for Dermatological Research

Amount: EUR 25,000

Grant category: Research Networking

Year: 2024

Geography: Switzerland

The 2024 ESDR Academy for Future Leaders in Dermatology entitled “Translational innovation in dermatology” will be held 10-12 October 2024 in Uppsala, Sweden. The goal of this initiative is to foster excellence in academic dermatology and encourage gifted young dermatologists to further pursue their careers through guidance and mentoring. The program is primarily open to European residents currently engaged in skin-related research (MD, PhD, Post-Doc). The selected applicants will give oral presentation of their work and current research. The program will be completed by talks from selected senior scientists, from Future Leaders alumni serving as mentors and from guest speakers. Besides scientific sessions there is a strong emphasis on encouraging young people to network and to exchange ideas.

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Single-cell ribosome profiling to monitor the translational landscape in skin wound healing

Grantee: Ataman Sendoel, Assistant Professor, University of Zurich

Amount: DKK 3,979,800

Grant category: Research Grants in open competition

Year: 2024

Geography: Switzerland

Ataman Sendoel’s project seeks to improve our understanding of how genes are translated to protein during wound healing and clarify the potential of the involved pathways as drug targets.

Impaired wound healing poses a substantial medical challenge, particularly among the elderly. Understanding the gene expression changes during wound repair is therefore essential for devising new strategies to enhance wound healing in aging and disease.

While transcriptional (i.e., going from DNA to messenger-RNA) control has been extensively studied in the skin, recent studies have indicated that cellular behavior is strongly coupled to the regulation of translation (i.e., going from messenger-RNA to protein). However, how translation is controlled during wound repair and how its deregulation mechanistically contributes to impaired wound repair in aging remains unknown.

In this project, Ataman Sendoel and his team will exploit an in vivo strategy to comprehensively map the function of the translational landscape in skin wound healing. Leveraging a single-cell ribosome (an intracellular protein complex that translates messenger-RNA to protein) profiling strategy in vivo, the team will monitor skin cells during different wound healing stages. By coupling this with single-cell RNA sequencing, they will determine cell-type-specific translational efficiencies and identify factors relevant to wound repair in aging.

Finally, Ataman Sendoel and his team aim to carry out a mini-screen to identify FDA-approved drugs that selectively increase the translational efficiency of skin wound repair factors.

Collectively, these data will provide systematic insights into the translational landscape of skin wound repair, and how deregulated translation leads to impaired wound repair. It may also clarify if protein synthesis pathways could be targeted therapeutically to restore wound healing.