Grant category: Research Grants in open competition

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.

Grant category: Research Grants in open competition

Year: 2024

Geography: United Kingdom

Maria Alcolea’s project explores how the plasticity of skin cells is affected by aging. Maria Alcolea and her team will study the molecular pathways that modulate changes in cell behaviour throughout life. The ultimate aim is to identify new targets to improve tissue regeneration and delay the regenerative decline associated with human skin ageing.

The ability of epithelial cells to rewire their program of cell fate in response to tissue perturbations has emerged as a new paradigm in stem cell biology. This plasticity improves the efficiency of tissue repair by enabling differentiated/lineage committed cells to reacquire stem cell-like behavior in response to damage. However, despite obvious implications for skin regeneration, virtually nothing is known about how the plastic capacity of skin cells is affected by ageing, and whether this contributes to changes in the normal physiology of the epidermis at later stages in life.

Maria Alcolea’s project will investigate the impact of aging in skin cell fate plasticity by making use of a novel in vivo model that enables tracing the fate of epidermal cells from the earliest stages of commitment towards differentiation. Newly developed tools offers a unique opportunity to identify the mechanisms dictating epithelial cell fate plasticity and determine whether aged-associated changes in this process hold the key to understand why the regenerative capacity of our skin declines over time. She will combine the lab’s expertise in in vivo quantitative lineage tracing, single-cell RNA sequencing approaches, and mathematical network analysis. Observations made in in vivo mouse models will be compared to human skin using a novel 3D organ culture.

Maria Alcolea’s project may contribute significantly to the emerging field of epidermal cell plasticity and provide a benchmark for identifying potential targets to partially reduce/reverse skin ageing.

Grant category: Research Grants in open competition

Year: 2024

Geography: Belgium

Sophia Maschalidi’s project explores the significance of enhancing efferocytosis – clearance of apoptotic cells by phagocytes – in skin injury repair, with the overall aim of accelerating wound closure.

The continual turnover of billions of cells in our bodies occurs as professional and non-professional phagocytes engulf cells dying via apoptosis. The efficiency of cell clearance or efferocytosis is remarkable and critical for homeostasis, minimizing inflammation and promoting repair. As the largest organ in our body, the skin acts as our first line of defense. Tissue repair after skin injury involves the clearance of apoptotic cells by phagocytes at the wound site as part of the process of resolving the inflammation and restoring the barrier. The importance of hastening barrier restoration is highlighted in chronic non-healing wounds, such as those associated with diabetes or in excess healing reactions after wounding leading to pathological scar tissue formation or fibrosis.

Sophia Maschalidi’s project aims to develop appropriate tools to enhance efferocytosis in vivo. Using novel techniques and sophisticated genetic mouse models, it will systematically address, for the first time, the importance of boosting efferocytosis during primary skin injury repair and in subsequent challenges. It will address how primary phagocytic experience shapes long-term changes on phagocytes and neighboring cells and whether this “efferocytic memory” shapes responses to secondary assaults.

Sophia Maschalidi’s project hopes to result in a fundamental understanding of the mechanisms and potential in boosting efferocytosis for therapeutic benefit in cutaneous wound management.

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.