Grant category: Research Grants in open competition

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Beth McLellan’s project, in collaboration with co-PI and Kosaku Shinoda, explores the functional interactions of live or viable bacteria within the skin microbial community, and their implications in skin disease. The project aims to develop a robust ex vivo model, Skin Microbiome in a Test tube (SMT), to study the dynamic biochemical activity of the viable skin microbiome. Preliminary data indicate that the prototype version of the SMT system (v1) is capable of preserving the diversity of skin bacteria ex vivo. The aims are to (1) refine SMT using Propidium Monoazide (PMA) sequencing to exclusively replicate the viable microbiome and (2) investigate the impact of skin microenvironmental factors (e.g., moisture, sebum levels, and skin breakdown) on the composition and biochemical activity of the viable microbiome, using data from non-invasive sensors at multiple skin sites.

With the generation of the improved version of the SMT (v2), the project hopes to create an innovative platform for functional skin microbiome studies, drug screening and pharmacokinetic modeling with an emphasis on microbial viability leading to individualized treatment strategies based on microbiome community profiles. SMT will serve as a foundation for identifying biomarkers, developing microbiome-based therapies, and improving pharmacokinetic predictions.

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Ann-Marie Schoos’ project explores atopic dermatitis (AD), which affects about 1 in 5 children. The disease burden of AD varies; some outgrow their disease while others have persistent symptoms. The reasons behind these different outcomes are not well understood and are not addressed by current treatments. Biological markers (biomarkers) can help us understand the disease better and, ideally, help predict, prevent, or treat it more effectively. Proteins can be used as biomarkers and appear in the blood due to secretion or cell damage. While there have been studies identifying such biomarkers (using proteomics) in adults, there is limited research on children, especially in relation to the early stages of AD. To understand the processes involved in early development of AD, Ann-Marie Schoos’ project will explore a novel, large-scale panel of blood-borne proteins measured before and after disease development (at birth, 6 months, 18 months, and 6 years of age) in the well-characterized COPSAC2010 cohort. The children of this cohort have been followed intensely throughout childhood with longitudinal (i.e., over time) measurements of inflammation, allergy, immune data, and genetics among others.

Ann-Marie Schoos’ project hopes to show that a simple blood test in early childhood can predict which children are at high risk of developing AD and who will have a severe and persistent disease course. This could lead to personalized prevention or treatment strategies, improving the quality of life for these children.

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Erin Chen’s project aims to address the fundamental question: how do we translate the composition of our body’s colonizing microbes (our microbiome) into insight about immune function? Commensal bacteria (commonly known as just “commensals”) colonize our skin, over our entire lives, and generate the vast majority of microbe-host encounters, with largely unknown consequences. Erin Chen’s project focuses on commensals’ interactions with T cells because these cells critically impact many aspects of health and disease. Unlike infections, where a single pathogen invades into the tissue, commensals colonize within complex communities and communicate to the host immune system across an intact skin barrier. How the immune system decodes signals from each member of this community is unknown. Erin Chen and her team will address this by colonizing mice with defined communities of commensals and tracking the commensal-derived antigens along with the strain-specific T cells. To do this, they will develop novel methods to detect commensal-derived antigens within the host tissue, at high resolution. By varying the abundance and composition of community members, they aim to discover novel antagonistic, synergistic, and emergent properties of commensal-specific T cells. This work will provide visibility into a currently invisible process: how a lifetime of commensals on our skin are constantly sculpting our T cell function, which ultimately impacts our susceptibility to infections, autoimmunity, and cancer.

Grant category: Research Grants in open competition

Year: 2024

Geography: United Kingdom

Clare Bennett’s project explores the skin’s sensory nerves. These protect us from harm, such as heat or toxins, yet little is known about how they are sustained. Psoriasis is a common disfiguring skin condition, where pain suffered by patients and its impact on mental health and quality of life are frequently overlooked. Understanding how sensory nerves are protected in healthy skin could reveal why this process fails in psoriasis, leading to pain. Langerhans cells (LCs), immune cells in the skin’s epidermis, are known for detecting infections. However, emerging evidence suggests that LCs may also perform non-immune roles that have not been thoroughly studied. This project aims to investigate how psoriasis changes the way LCs interact with the nerves in the skin. Clare Bennett and her team hypothesize that changes in psoriatic skin disrupt protective function, leading to uncontrolled nerve growth. Clare Bennett and her team combine expertise in immunology, neuroscience, and dermatology. They will use advanced microscopy, genetic models, and gene expression analysis in well-established lab models to study LC-nerve interactions and aim to validate their findings using psoriasis patient skin samples. The results of Clare Bennett’s project could fill critical gaps in our understanding of sensory nerve regulation. Ultimately, the hope is to uncover new strategies to reduce pain and improve quality of life for psoriasis patients and potentially those with other skin diseases.

Grant category: Research Grants in open competition

Year: 2024

Geography: United Kingdom

This project concerns establishing a consortium for research in the genetics of skin diseases, which are the 4th leading cause of disability globally. Lavinia Paternoster and the group behind the Skin Genetic Consortium (SGC) will use population-scale genomic datasets from across the globe to conduct well-powered human genetic studies to discover disease mechanisms, identify and prioritize drug targets, and improve the accuracy and utility of skin disease diagnoses for epidemiological research. Recent years have seen a dramatic increase in the number and diversity of population biobanks across the globe. The SGC will leverage these resources to undertake genome-wide association studies for an extensive set of skin conditions. Sample sizes in excess of 4 million will increase power for gene discovery in many previously understudied skin conditions. Furthermore, cross-disease analyses will be performed to identify shared disease mechanisms, potentially revealing drug re-purposing opportunities. The SGC brings together experts in genetic epidemiology, clinical dermatology and cohort custodians. This first phase of the SGC will uncover key biological insights and drug target evidence for an initial set of common skin conditions.

The project aims to generate a platform for uploading and harmonizing data, performing streamlined genetic analysis and open distribution of results. With further funding the SGC will expand to increase participant diversity, extend analyses to rare variants and generate additional molecular functional genomics data for experimental validation and clinical translation of results.

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.

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.

Grant category: Research Grants in open competition

Year: 2024

Geography: France

Rebecca Deprez-Poulain’s project aims to investigate the therapeutic potential of ERAP1 and ERAP2 inhibitors for the treatment of psoriasis.

Psoriasis is caused by the erroneous recognition by T-cells of the immune system of self-peptides called antigens presented at the cell surface by the HLA-C receptor. This results in destruction cells and subsequent chronic inflammation. ERAP enzymes, which are the main actors of antigen preparation within cells, influence the immune response, and genetic studies show that several ERAP variants predispose to psoriasis. Rebecca Deprez-Poulain has identified selective inhibitors of ERAP1 and ERAP2 which decrease antigen presentation and T-cell activation and show preliminary positive results in vivo. Her project will combine structural biology, medicinal chemistry, biochemistry, and cellular biology to optimize current compounds into potent and selective inhibitors targeting ERAP. It will assess their therapeutic potential in purposely designed transgenic mouse models containing human ERAP, as well as in patient cells.

Rebecca Deprez-Poulain’s project may define the optimal profile of an ERAP inhibitor as a pharmacological tool, providing a foundation for the exploration of ERAP roles and eventually an ERAP-based oral treatment for psoriasis.

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.

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Jeffrey Rasmussen’s project investigates the mechanisms governing Langerhans cells’ immune response in wound healing, particularly the role of the microtubule cytoskeleton.

Skin provides a robust and durable physical barrier essential for regulating hydration and repelling pathogens. Damage to skin must be rapidly resolved to maintain organ homeostasis. Epidermal-resident immune cells known as Langerhans cells use dendritic protrusions to dynamically surveil the skin microenvironment, which contains epithelial keratinocytes and somatosensory peripheral axons.

The mechanisms governing Langerhans cell dendrite dynamics and responses to tissue damage are not well understood. Jeffrey Rasmussen and his lab have developed a tractable system using adult zebrafish to study Langerhans cell dynamics. Initial studies using this system revealed several new discoveries, including: 1) that Langerhans cells are the primary phagocyte for degenerating somatosensory axons; 2) Langerhans cells undergo stereotyped responses to local and tissue-scale keratinocyte wounds; and 3) the actin regulator ROCK regulates key aspects of Langerhans cell wound responses. Despite advances in identifying mechanisms of actin function in Langerhans cells, roles for the microtubule cytoskeleton in Langerhans cell biology remain essentially unknown. In preliminary studies, Jeffrey Rasmussen has developed a novel transgenic reporter for microtubules in Langerhans cells and found that the microtubule cytoskeleton dynamically reorganizes during wound responses. His project aims to determine how the microtubule cytoskeleton contributes to the intracellular trafficking and dynamic wound responses of Langerhans cells.

The results of Jeffrey Rasmussen’s project could lead to new fundamental understandings of Langerhans cell biology and dynamics.