Explore our grantees and awardees

Grant category: Research Grants in open competition

Year: 2023

Geography: Denmark

In this project Mariaceleste Aragona, in collaboration with Elena Enzo (University of Modena and Reggio Emilia, Italy), aims at the optimization of skin graft production for regenerative and replacement purpose.

Skin grafts for transplantation purposes are generated from epidermal stem cells. These regenerative therapies are life-saving procedures and have been demonstrated to be successful and safe for the treatment of burns and severe genetic diseases. Long lasting skin regeneration requires the correct amount of stem cells (SCs) in the graft. However, the treatment of large burns or skin replacement therapy in elderly patients are still challenging.

In such situations, the limited area of donor sites, and the physiological reduction of the number of SCs results in insufficient availability of SCs for graft production. A way to efficiently produce more SCs is to enforce their self-renewing – the process of generating more SCs – capacity.

A condition that forces SCs to increase their self-renewal capacity is tissue stretching. In this project, Mariaceleste Aragona aims to generate a comprehensive atlas of the changes occurring in space and time during tissue stretching. Based on this atlas, they will elucidate the signaling molecules instructing SC’s self-renewal and identify options to target such molecules. This knowledge will be used to develop cell culture conditions to ameliorate skin graft productions for clinical application.

Collectively, such insights will provide new fundamental knowledge on the biology of SCs and this approach may improve the clinical success of skin regenerative and replacement therapies to the benefit of patients.

Grant category: Research Grants in open competition

Year: 2023

Geography: Sweden

Kilian Eyerich’s project aims to investigate the role of the transcription factor FOXO4 in the development of a specific type of T cells – the Th22 cells.

Th22 cells are a distinct subset of CD4+ T helper cells, and their effector cytokine IL-22 plays a protective role in barrier homeostasis by regulating innate immune responses, antimicrobial defense mechanisms, and wound healing. The natural differentiation of naive CD4+ T cells into the Th22 lineage and production of IL-22 by these cells is a multifactorial process that is not yet fully understood. In this project, Kilian Eyerich, along with colleague Kunal Das Mahapatra and team, will investigate the hypothesis that the transcription factor FOXO4 is a novel regulator of IL-22 production in Th22 cells. Pilot data show that FOXO4 is upregulated in human skin derived Th22 clones. It has a pattern of early induction and steady increment during Th22 differentiation, which is governed by the cytokines IL-6 and TNF-a. Moreover, the team has shown that silencing FOXO4 in naive T cells in a

Th22-inducing condition leads to reduced IL-22 secretion and that there is a protective effect of this regulation on epithelial cells, as observed in a scratch assay where keratinocytes, cultured in the supernatant from FOXO4-depleted T cells, migrated less efficiently.

The proposed project therefore aims to perform a deeper characterization of FOXO4 in Th22 cells by systematically identifying FOXO4-regulated genes, downstream pathways, and potential co-factors. In addition, the extrinsic role of FOXO4 on keratinocytes and skin wound healing will be assessed by ex vivo assays and analysis of multi-omics data from human patients.

Taken together, this project may offer novel insights into the regulatory processes in development and function of Th22 T cells.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Joshua Moreau’s project investigates the potential role of B cells (antibody-producing immune cells) in the inflammatory skin disease, hidradenitis suppurativa to create a foundation for future therapeutic approaches.

Hidradenitis suppurativa (HS) is a painful skin disease characterized by highly inflamed lesions. While the causes of lesion progression are not well understood, this inflammation is often marked by accumulation of an immune cell subset called B cells. In certain contexts, B cells cause damage to the body and perpetuate inflammatory responses, however, for this to happen these cells need to undergo a process of maturation to become antibody-producing plasma cells. In this project, Joshua Moreau aims to understand if B cells accumulating in HS affected skin mature into disease perpetuating plasma cells.

To do this, Joshua Moreau and his team will utilize a technique called spatial transcriptomics technology that allows them to track B cell maturation across a skin sample. This, in turn, will allow them to determine if plasma cells originate at the site of inflammation in the skin.

Additionally, the team will explore avenues for blocking B cell maturation specifically within the skin using advanced human skin tissue culturing approaches.

Collectively, these experiments may provide currently missing insight into the disease-causing potential of B cells in HS and form a foundation for targeting them therapeutically.

Grant category: Research Grants in open competition

Year: 2023

Geography: Denmark

Hans Wandall’s project aims to investigate the potential role of sugar molecules (glycans) in inflammatory skin diseases.

Several skin diseases, including atopic dermatitis, contact dermatitis, and psoriasis, are caused by a cascade of inflammatory events localized to the epidermis and the dermis.

Based on substantial preliminary findings showing dysregulation of glycosylation (sugarcoating) of the cells in the skin of patients with inflammatory skin diseases, Hans Wandall and his team hypothesize that carbohydrate receptors on immune cells recognize inflammation-induced glycan changes and induce a vicious cycle that aggravates inflammatory skin diseases in susceptible individuals.

They will investigate this through a three-pronged approach: 1) characterize the glycosylation patterns of skin samples obtained from patients diagnosed with contact dermatitis, psoriasis, and atopic dermatitis, and also analyze glycosylation patterns on human keratinocytes and fibroblasts from skin-inflammation models based on human 3D organ-like skin systems with exogenous cytokines and inflammatory cells and samples from murine models of inflammatory skin diseases. 2) Next, they will co-culture immune cells with keratinocytes ablated for select glycosylation pathways to define the functional role these in relation to glycan changes, and finally, 3) analyze the importance of key immune receptors sensing the glycan changes.

Through the investigations, the project will systematically evaluate the role of glycans in inflammatory skin diseases with a promise to provide new targets for interventions.

Grant category: Research Grants in open competition

Year: 2023

Geography: Switzerland

This project by Hans-Dietmar Beer aims to elucidate the molecular mechanisms associated with NLRP1 inflammasome activation in keratinocytes in inflammatory skin conditions.

Inflammasomes are protein complexes, which are mainly expressed by immune cells. Upon detection of stress factors, they regulate activation of the proinflammatory cytokine proIL-1β and its release to the extracellular environment, thereby inducing inflammation. Inflammasomes are required for initiation of normal immune responses, however, their chronic activation also underlies the pathogenesis of numerous inflammatory diseases.

The epidermis, the outermost layer of our skin, represents the first line of defense of the human body and consists of densely packed layers of keratinocytes. These cells express high levels of all proteins of the NLRP1 inflammasome. To address the roles of this inflammasome in human skin, Hans-Dietmar Beer and his team previously activated NLRP1 in keratinocytes cultivated together with dermal fibroblasts (connective tissue cells) in a three-dimensional (3D) organotypic skin model and found that NLRP1 activation induced an altered tissue phenotype and activation of pathways associated with inflammatory skin diseases. Most importantly, the team also detected inflammasome activation in keratinocytes in biopsies of patients suffering from these conditions.

The preliminary results suggest that inhibition of NLRP1 activation in keratinocytes might represent a novel therapeutic strategy for patients with certain inflammatory skin diseases and the current proposal seeks to investigate this hypothesis in more detail.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

The project of Emma Guttman aims to develop an improved understanding of the molecular basis of chronic hand and foot eczema to guide future treatment approaches.

Chronic hand and foot eczema is a highly prevalent disorder, affecting up to 15% of the overall population, and represents an enormous socio-economic and psychosocial burden. The condition is often refractory to conventional treatments. In addition, chronic hand and foot eczema shows considerable inter- and intra-patient heterogeneity, further complicating treatment options.

Importantly, overall pathophysiological mechanisms are still only insufficiently understood, as skin biopsies from these areas are very difficult to obtain due to the location in which it may implicate local pain, wounds, and visible scars. Thus, better sampling methods are urgently needed.

Emma Guttman and her team propose to use tape stripping, a non-invasive method that targets the outermost layers of the skin, to collect lesional and non-lesional skin samples. Through a multi-omics approach, including transcriptomic (looking at gene expression) and multiplex proteomic methods (looking at active proteins), these samples will be used for improved molecular and genetic understanding of chronic hand and foot eczema. Their study will include samples from adult patients with different forms of chronic hand and foot eczema, stratified for specific locations, severity, and clinical subtypes. Results will be compared to matched healthy control individuals.

If successful, results obtained from Emma Guttman’s investigation may identify disease-causing factors specific for chronic hand eczema subsets and locations, that could guide future targeted treatment approaches in a more personalized or stratified manner.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Charles (Chiwei) Xu’s project aims to investigate the molecular basis for cutaneous neuropathies (i.e., sensation of pain, numbness or fatigue caused by neural damage).

Mouse skin contains a dense network of nerve endings and is a good system to study interactions between the peripheral nervous system and barrier tissues in mammals. Intriguingly, axons (the elongated, signal-transducing sections) of sensory neurons are closely associated with hair follicle stem cells (HFSCs) in the skin, and Charles Xu has identified ligand-receptor pairs that mediate signaling between the two cell types. Specifically, he has identified the HFSC-derived parathyroid-hormone-like hormone (Pthlh) as a top candidate factor required for sensory innervation. Charles Xu has also established that Pthlh signals through the receptor Pth1r in sensory neurons. To further study crosstalk between HFSCs and sensory neurons, he has established a 3D co-culture system of these cells. Using that system, he aims to further characterize Pthlh-Pth1r signaling in the context of direct HFSC-sensory neuron interactions in vitro. He also aims to investigate the physiological relevance in an in vivo mouse model. In doing so, Charles Xu and his team aim to establish a versatile technical platform to study cutaneous neuropathies, which are common disorders where there is currently a lack of both mechanistic understanding and effective treatment.

Grant category: Research Grants in open competition

Year: 2023

Geography: Spain

Allergic contact dermatitis (ACD) is a frequent skin condition associated with significant loss of quality of life. Finding specific biomarkers has emerged as a relevant challenge to improve the diagnosis of patients and unravel therapeutic alternatives.

Recent findings have highlighted the existence of allergen-specific transcriptomic fingerprinting (i.e., genetic patterns that enable unambiguous identification of entities – here allergens). However, to date only a few studies have been performed comparing a wide range of different allergens.

In the proposed project, Ana Giménez-Arnau, along with colleague David Pesqué, plans to make a gene expression analysis of biopsies from patch-induced ACD by methylisothiazolinone, diazolidinyl urea, nickel, isoeugenol and 2-hydroxi-ethylemetacrylate. Specifically, Ana Giménez-Arnau and her team will evaluate the presence of allergen-specific genetic fingerprinting, if common biomarkers between allergens can be identified, if there are transcriptomic changes depending on the biopsy timing and finally, they will correlate the results with the characteristics and intensity of inflammatory infiltrates and the level allergic reaction of the patch-induced ACD.

This prospective investigation will be based on recruitment of patients with ACD to the indicated allergens and includes two single patch tests containing the standard commercialized allergen and one single patch test with petrolatum (positive control) to be applied on day 1. Two biopsies will be taken on day 3 (one from the petrolatum patch and one from the first allergen patch). The final biopsy will be taken on day 5 from the remaining allergen patch.

Collectively, the project will provide insights to the genetic characteristics of allergic contact dermatitis and may provide a foundation for identifying common or allergen-specific treatment targets.

Grant category: Research Grants in open competition

Year: 2022

Geography: Germany

The aim of Catherin Niemann’s project is to understand the biologic events during sebaceous gland differentiation, tissue remodeling, and regeneration.

Sebaceous glands (SGs) are critical for the physiological balance and barrier function of mammalian skin. SG dysfunction is associated with a variety of skin diseases, including acne. Despite recent advances using mutant mouse models with SG defects, the main drivers of normal SG functions remain incompletely understood. Therefore, a better understanding of how SG physiology and sebum production (an oily mixture produced by sebocytes, cells of the sebaceous gland) are regulated, is a clinical necessity.

Using both in vivo and in vitro models, Catherin’s project will focus on the regulation of SG stem cells, which are the primary responders to stimuli at the interface with the tissue environment. In vivo, Catherin and her team will use a combination of genetic mouse models and high throughput technologies to identify key players controlling normal SG activity. In vitro, the team has developed a 3D cell culture model that will be modelled to mimic SG differentiation to uncover and validate the central mechanisms of SG regulation. This SG-organoid model will be especially beneficial to decipher the specific role of extra-cellular matrix components in SG physiology and to examine the interaction with other cell types, including immune cells, for their impact on SG cell differentiation and contribution to SG defects in disease settings.

The long-term goal of the project is to establish a platform for testing new therapeutic strategies for the treatment of SG disorders.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

This project initiative by Richard Granstein extends research previously funded by the LEO Foundation into the role of calcitonin gene-related peptide (CGRP) in regulating skin immunity by acting on endothelial cells (ECs – the cell type which lines the interior wall of blood vessels) and aims to elaborate on this regulation by studying the potential involvement of non-skin located ECs.

Recent studies have defined a novel pathway by which CGRP can skew the outcome of an immune response away from one type of T-cell mediated immunity (Th1-type) and toward another type (Th17-type) through actions on ECs. This work was originally done in cell cultures but subsequent studies using mice specifically lacking functional CGRP receptors on ECs found that this pathway indeed operates in vivo. Immunization of these mice led to decreased generation of Th17-type T cells in regional lymph nodes, but increased generation of Th1-type helper T cells. In addition, these mice were found to have severely depressed contact hypersensitivity responses. It is not known if the reduction in contact hypersensitivity responses relates to the observed changes in T helper cell differentiation. These results suggest that it may be possible to therapeutically manipulate diseases involving Th17 mechanisms, such as psoriasis, and, perhaps, other hypersensitivity disorders affecting the skin.

Given these results, it will be important to know more about the physiology of this novel pathway. Preliminary data suggest that ECs not in the skin may be sufficient targets for CGRP to exert the effects seen on T helper cell responses. Richard’s project proposes experiments to 1) test the hypothesis that ECs within regional lymph nodes are sufficient for the T helper cell effect observed in vivo and 2) to further define the mechanisms by which contact hypersensitivity is reduced in mice lacking functional CGRP receptors on ECs. Ultimately, these studies may suggest novel new routes for therapies.