Grant category: Research Grants in open competition

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.

Grant category: Research Grants in open competition

Year: 2022

Geography: Spain

This project led by Xavier Gasull, also Professor at the Neuroscience Institute of the University of Barcelona, seeks to investigate and validate the potential of a newly identified target molecule on sensory nerves of the skin for treatment of chronic itch.

Chronic itch is a very important problem for patients suffering from several dermatologic diseases such as psoriasis, atopic dermatitis, or dry skin. Constant skin scratching in response to itching may further worsen the skin lesion.

In all these dermatological conditions, pruritic (itching) stimuli activate specific sensory neurons in the skin that send the message to the brain, where the sensation of itch is perceived and trigger the scratching response. The recent description of the specific sensory neuron subpopulations involved in this process has started the elucidation of some of the neural mechanisms involved in itch signalling.

From recent RNA sequencing databases and the functional characterization of itch sensing neurons, Xavier and his team have identified a new pharmacological target that can be used to decrease neuronal activation and relieve itch sensation. They have also identified a candidate drug activating this pharmacological target, which shows positive results decreasing acute and chronic itch not mediated through histamine, for which no effective drugs exist to date.

The focus of this project is to validate this new target in different skin disease models that produce chronic itch. They will use computational methods to design new drugs against this target, synthesize and then test them for therapeutical purposes. The hope is to benefit patients suffering from chronic itch in different skin diseases and, if successful, will add new pharmacological regimes for treating chronic itch.

Grant category: Research Grants in open competition

Year: 2022

Geography: Denmark

Nils Færgeman’s proposal investigates the role of acyl-CoA binding protein (ACBP) in regulating dermal white adipose tissue function in the skin.

Dermal white adipose tissue (dWAT) is a distinct type of fat depot located under the reticular dermis (the deepest layer of the dermis) and comprises a special layer of the skin. Compared to other well-defined fat depots, dWAT shows a very high degree of plasticity, and can rapidly and locally expand and reduce its volume in response to various stimuli.

Via lipolysis (an enzymatic process that releases free fatty acids from triglycerides in fat depots) dermal white adipocytes (fat cells) release fatty acids into the extracellular space, which for example can regulate production of extracellular matrix in dermal fibroblasts and differentiation of keratinocytes.

Recently, Nils and colleagues have demonstrated that acyl-CoA binding protein plays a fundamental role in lipid metabolism in the skin and is indispensable for its barrier function. Given that ACBP is required for differentiation of white adipocytes and given its high expression in the skin, the hypothesis behind this project is that ACBP plays a critical role in dermal adipose tissue by serving as a key regulator and driver of intracellular fatty acid metabolism.

The group will use state-of-the-art lipidomics (global analyses of lipid composition and abundance) and genomics technologies and a series of novel mouse models, to clarify the role of ACBP in dWAT functions in the skin and to define the role of dWAT in systemic energy metabolism.

Grant category: Research Grants in open competition

Year: 2022

Geography: Denmark

This project led by Lotte K. Vogel aims to elucidate the role of the protease matriptase (an enzyme that cleaves proteins) in a variant of Ichthyosis, a common skin disease that causes “fish-scale” like skin with poor treatment options.

The molecular mechanisms behind ichthyosis are not understood, but variations in several genes may cause ichthyosis. Variants of the ST14 gene, which encodes the serine protease matriptase, lead to a type of ichthyosis called Autosomal Recessive Congenital Ichthyosis 11 (ARCI11). The prevalence of ARCI11 is elusive at present.

Lotte and her team’s preliminary data show that ARCI11-related matriptase variants are unable to activate a certain substrate (a protease on its own), suggesting that ARCI11 is caused by a lack of activation of this protease. Results from the group also suggest that inactivation of a certain enzyme cascade leads to Ichthyosis. Surprisingly, for several enzymes in this cascade both the zymogen form and the activated form of the enzyme exhibit proteolytic activity.

In this project, Lotte aims to investigate the importance of matriptase in ARCI11 through a three-pronged approach: (1) by elucidating whether a protease located downstream of matriptase in the same pathway can be activated by an appropriate soluble enzyme which is suitable for topical application to the skin. (2) by elucidating whether ARCI11 is caused by a difference in substrate preferences between the zymogen form and the activated form of these enzymes and (3) by systematically screening for genetic variants of matriptase causing ARCI11 and estimating their frequency in the population. The genetic material to do a more systematic search for ARCI11-causing variants of matriptase and estimate their frequency Is already available.

If successful, Lotte’s project will make a solid and original contribution to the understanding of ichthyosis that may lead to improved treatment options.