Grant category: Research Grants in open competition

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.

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.

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.

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.

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Wei Tao’s project explores the biological mechanisms to improve wound healing in adults by mimicking the scarless fetal wound healing process. This project aims to engineer a system that replicates the fetal extracellular matrix and immune responses, using mRNA techniques to produce specific proteins and inhibit biological processes leading to scar formation. This system employs lipid nanoparticles for mRNA delivery and hydrogel for controlled release, enabling spatiotemporal control of key components like collagen type III and interleukin-10, thereby reconstituting fetal-like extracellular matrix organization and modulating over-activated immune responses.

The project’s goals include establishing a foundation for future scarless wound healing studies, developing a hybrid mRNA therapeutic platform for skin defects and diseases, and correlating extracellular matrix and immune modulation with subsequent biological processes and outcomes. This research has promising potential for clinical applications in wound care and other dermatological diseases.

Grant category: Research Grants in open competition

Year: 2024

Geography: Sweden

Niclas Roxhed’s technology-focused project aims to investigate the potential of spiked microspheres as vehicles for large-molecular drug delivery into skin to treat diseases.

Modern biologic drugs have transformed the way we treat many diseases. However, these drug molecules are too large to pass biologic barriers and therefore need to be injected. For skin diseases, the outermost skin layer effectively prevents larger molecules from entering the skin.

To address this problem, Niclas Roxhed and his team have tailor-made ultra-sharp spiked microspheres that painlessly penetrate only the outermost skin layer and allow delivery of large molecules into skin. In this project, they will use these spiked microspheres in an atopic dermatitis model to topically deliver large-molecular nucleic acids and nanocarriers to inhibit inflammatory reactions. To verify effective delivery, Niclas Roxhed and his team will quantify inflammatory markers in skin using micro-sampling and proteomics profiling.

The results could form the basis for highly effective delivery of biopharmaceuticals as topical creams and potentially revolutionize treatment strategies in skin disease.

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Rosaria Gandini’s project investigates the molecular details of the IgE-FceRI complex and its functioning on mast cells and basophils in order to improve treatment opportunities for urticaria.

Urticaria, a common inflammatory skin disorder characterized by itchy wheals, angioedema, or both, manifests in acute (AU) and chronic (CU) forms. It significantly impairs patients’ quality of life, causing sleep disturbances due to pruritus, fatigue, and anxiety. The symptoms arise from the activation of skin mast cells and basophils, leading to the release of histamine and other inflammatory mediators. This activation is initiated by cross-linking and clustering of the complexes between immunoglobulin E (IgE) and its high-affinity receptor, FceRI, which is expressed on the surface of these cells.

The FceRI-IgE complex hence acts as a powerful molecular switch, which initiates the inflammatory cascade and thus provides an attractive target for drug intervention. The structural basis of this activity, however, remains open.

Rosaria Gandini’s project aims to determine the structure of the FceRI-IgE membrane complex using state of the art Cryo Electron Microscopy (cryo-EM).

Successful elucidation of the molecular details of the entire complex and its conformations will allow identification of specific regions on FceRI for targeted intervention. This knowledge will deepen the understanding of the interaction of antibodies with Fc receptors in general and may pave the way for the development of specific and effective treatment of urticaria and related disorders.

Grant category: Research Grants in open competition

Year: 2024

Geography: Sweden

Jakob Wikstrom’s project aims to improve the understanding of mitophagy, a process where damaged and aged mitochondria are removed and recycled intracellularly, in relation to wound healing.

In the event of abnormal wound healing, chronic wounds may form and thereby place a large burden on healthcare systems. Importantly, treatment options remain limited owing to the complex nature of chronic wound pathogenesis, meaning alternative avenues need to be explored in the quest to develop novel therapies.

One avenue that Jakob Wikstrom and his team aim to pursue is that of targeting mitochondria and in particular, the quality-control process of mitophagy. Mitochondria play vital roles required for efficient wound healing, most notably in regulating metabolism. However, the role of mitophagy in wound healing is poorly understood, and only a few studies have studied it in human tissue.

Interestingly, preliminary data from human tissue and primary human cell culture for this project shows that mitophagy plays an important role in the early- and mid-wound healing stages, and that mitophagy induction aids in fibroblast and keratinocyte migration. However, the precise mechanisms of how mitophagy is required in these cell types during wound healing is yet to be elucidated.

Jakob Wikstrom and his team aim to evaluate the mechanistic role of mitophagy in wound healing through a variety of experiments on relevant human cell types, investigating metabolism, chronic inflammation, and gene expression, as well as comprehensively disseminating the impact of mitophagy on wound healing in mouse models.

Successful implementation of this project could provide novel ideas for and facilitate the development of future mitochondria-targeted wound treatments.