Digging deep for filaggrin’s function in regulating epidermal barrier formation

Grantee: Ellen van den Bogaard, Professor, Radboud University Medical Center

Amount: DKK 3,929,813

Grant category: Research grants in open competition

Year: 2022

Geography: Netherlands

The aim of Ellen’s project is to improve the understanding of the role of skin protein filaggrin (FLG) in regulating and controlling epidermal keratinocyte robustness and differentiation.

Ever since the discovery that loss-of-function mutations in the FLG gene are the main risk factor for developing Atopic Dermatitis (AD), many studies have aimed to relate the presence or absence of FLG to processes involved in skin homeostasis. The filaggrin protein is comprised of several repetitive elements as well as two unique domains, A and B. While many mutations in the filaggrin monomers are known to be important in AD, the role of the A and B domains have been less studied.

Previous investigation, featuring collaborator and postdoctoral fellow Jos P.H. Smits, discovered that mutations in these domains affect the expression of genes that are important for terminal differentiation of epidermal keratinocytes. The terminal differentiation of keratinocytes is important for the formation of the skin barrier. In this project, the team want to expand initial findings into elaborate studies using 3D skin organoids, also called “human skin equivalents” combined with in-depth molecular and functional analyses. Ellen’s group has developed many of these 3D skin equivalents to resemble both the structure and environment of real skin. By exposing the skin equivalents to relevant environmental factors, they will study how mutations in the filaggrin A and B domains affect keratinocyte differentiation and terminal fate and ultimately the overall skin barrier function. The hope is to identify potential new targets for therapeutic interventions in AD by modifying the expression of filaggrin and thereby regulating the barrier function of the skin.

Single Cell Transcriptomic Classification of Inflammatory Skin Disease

Grantee: Jeffrey Cheng, Associate Professor, The Regents of the University of California San Francisco

Amount: DKK 3,999,960

Grant category: Research grants in open competition

Year: 2022

Geography: USA

Jeffrey Cheng’s project aims to improve our understanding and discrimination of chronic atypical skin rashes which do not fit into well-defined clinical categories. Jeffrey along with his team will approach this by first mapping gene expression variations on a single cell level for a number of prototypical rash types. This will allow them to create a framework to identify variations that can discriminate between well characterized rash types, which each have different treatment regimens. While they have already done this for rashes with atopic dermatitis- and psoriasis-like features, this project will add information about rashes with features common to cutaneous sarcoidosis and lupus erythematosus. Based on these findings, Jeffrey aims to establish a more accessible approach to classify these rashes by assessing tissue samples for presence of disease-relevant proteins.

If successful, Jeffrey and his team will provide important guidance for optimal classification and subsequent treatment of otherwise indeterminant rashes.

Deliniating the functional role of ERAP2 and HLA-C in the pathogenesis of psoriasis

Grantee: Claus Johansen, Associate Professor, Aarhus University

Amount: DKK 3,230,325

Grant category: Research grants in open competition

Year: 2022

Geography: Denmark

Claus Johansen’s project investigates the role of the protein ERAP2 in the pathogenesis of psoriasis.

Psoriasis is considered an autoimmune disease – i.e., a disease in which the T-cells of the immune system attack and destroy the body’s own cells by error. During an exposure to external factors (peptides, bacteria etc) a system of specialized cells engulfs, digests, and presents peptide fragments (antigens) of these external factors on their surface to the body’s immune cells – usually cytotoxic CD8+ T-cells – which, once activated, then surveil, identify, and destroy foreign elements containing that specific peptide or peptides with very similar overall structure. The peptides are presented by a specific receptor, called the human leukocyte antigen (HLA) receptor and it is well-known that a particular subtype of this receptor, the HLA-C receptor is dominant in psoriatic patients – still, concrete disease-specific self-antigens have not yet been identified. Recent results have indicated that a protein, ERAP2, which facilitates the association of antigen peptides to HLA receptors may have a role to play in the erroneous recognition of self-antigens in autoimmune diseases like psoriasis. Claus and his team aim to clarify the role of this protein in the current proposal.

If successful, their project may help shed further light on the autoimmune characteristics of psoriasis – and eventually help guide new treatment approaches.

The aryl hydrocarbon receptor integrates signals from the commensal yeast Malassezia to attenuate inflammation in the atopic skin

Grantee: Salomé LeibundGut-Landmann, Professor, University of Zurich

Amount: DKK 4,199,654

Grant category: Research grants in open competition

Year: 2022

Geography: Switzerland

With this project, Salomé LeibundGut-Landmann along with collaborator Giuseppe Ianiri aims to investigate the importance of aryl hydrocarbon receptor (AhR) activation in relation to treatment of allergic skin reactions, including atopic dermatitis.

AhR is a so-called transcription factor, activated by cyclic (aromatic) compounds, which regulates cellular signaling. It is known that AhR is important for maintaining the skin barrier and a healthy cutaneous immune system and Salomé and her team propose that this, at least in part, is regulated by the release of such aromatic compounds by the commensal (non-pathogenic) and very common skin fungal class, Malassezia.

Using both human keratinocytes and mouse models, this hypothesis will be tested and the biosynthetic pathways of aromatic binding partners (ligands) for Ahr produced by Malassezia strains will be characterized.

If successful, the understanding of the interplay between commensal fungi as part of the skin microbiome and cellular maintenance of the skin barrier could provide novel approaches for treating allergic reactions and other skin inflammatory conditions, like atopic dermatitis.

En route to identifying peptide antigen triggers in psoriasis

Grantee: Asolina Braun, Senior Research Fellow, Monash University

Amount: DKK 4,007,900

Grant category: Research grants in open competition

Year: 2022

Geography: Australia

Asolina Braun, along with her team and colleagues Professor Anthony Purcell and Professor Johannes Kern, aims to identify and characterize the key self-antigens presented to autoreactive T-cells in psoriasis (PsO) patients. Specifically, she will look at molecules displayed by the major psoriasis genetic risk determinant to identify new treatment targets.

Psoriasis is believed to be an autoimmune disease in which T cells of the immune system recognize short protein sequences (antigens) from the body’s own cells and subsequently attack and destroy tissues inducing a chronic state of inflammation. The initial priming of the T-cells occurs when antigens are presented on the surface of cells by human leukocyte antigen (HLA) receptors, the same molecules that need to be matched in organ transplantations. Among the HLA molecules, the HLA-Cw6+ variant is particularly abundant in psoriatic patients (50% of all and 80% of early onset patients), and Asolina and her team aim to characterize the specific antigens presented by this particular HLA receptor to identify potential targets for future immune therapy like the induction of tolerance in food allergies. The team has already generated the peptide (antigen) library necessary to investigate targets and has created a transgenic mouse model containing the desired HLA receptor to present the antigens. They will also use patient-isolated T-cells to examine the responses and identify the most important peptide antigens contributing to the disease. In parallel, they will investigate if the original trigger of the autoimmune response is caused by peptides from virulent (disease-causing) strains of the environmental pathogenic bacteria, Streptococcus pyrogenes.

Deciphering the mechanistic underpins of the inflammation-to-proliferation phase transition in human skin wound healing

Grantee: Ning Xu Landén, Associate Professor, Karolinska Institutet

Amount: DKK 4,164,510

Grant category: Research grants in open competition

Year: 2022

Geography: Sweden

Ning Xu Landén’s project seeks to improve wound healing by identifying key regulators of cellular transition from inflammation to proliferation, a cardinal event during normal skin wound healing which is lacking in chronic wounds.

Ning and her team will approach this by mapping the spatiotemporal changes, both genetic, molecular and cellular, happening during the healing of acute wounds. Using this mapping, she and her team will then aim to identify the core genetic changes and intercellular crosstalk which regulates the inflammation to proliferation transition. Once identified, these changes and intercellular crosstalk will be characterized in more detail.

The ultimate goal is to identify the “master” regulators of inflammation-to-proliferation transition in order to improve and accelerate wound healing and thus minimize the risk of development of chronic wounds.

If successful, this project could pave the way for a novel approach to wound healing which may also eventually reduce subsequent scarring.

New therapy and diagnostics of psoriasis vulgaris and psoriatic arthritis based on new animal models

Grantee: Rikard Holmdahl, Professor, Karolinska Institutet

Amount: DKK 3,622,500

Grant category: Research grants in open competition

Year: 2022

Geography: Sweden

Rikard Holmdahl and his team have discovered that mannan, a large natural sugar molecule found in yeast and plant cell walls, can induce a psoriasis-like condition in mice which strongly resembles human disease in terms of both genetics and clinical presentation.

The aim of Rikard’s research is to investigate the potential of this animal model to improve our understanding of disease mechanisms, predict disease progression and potentially treat psoriasis and psoriatic arthritis by modifying the sugar structure of mannan – hereby increasing the cellular level of reactive oxygen species which appears to be protective against disease development and progression.

In addition, Rikard’s team aims to identify new diagnostic (auto-)antibodies, found both in the mannan-induced psoriasis (MIP) mouse model and in a cohort of psoriatic arthritis patients, to improve early diagnosis and hence improve intervention.

If successful, the results could provide a new and more exact tool to further investigate what causes psoriasis and psoriasis arthritis, while at the same time potentially improving the efficiency of early diagnosis and subsequent treatment.

Genetic mechanisms of acne vulgaris

Grantee: Michael Simpson, Professor of Genetics, King's College London

Amount: DKK 2,870,799

Grant category: Research grants in open competition

Year: 2022

Geography: United Kingdom

The aim of Michael Simpson’s project is to identify potential cellular or molecular targets for acne treatment, based on analysis of genetic variation found in a large pool of acne patients.

Acne vulgaris is a very common skin disease which is characterized by clogging and inflammation of the pilosebaceous unit, which consists of a sweat gland and a hair follicle including the hair itself. While various potential causes leading to the disease have been investigated over the years, the underlying disease mechanisms have not yet been sufficiently elucidated. One common approach to learning more about cellular and molecular causes for development of disease in some people is to investigate changes in the genes that influence the behavior and communication paths of cells – the signaling cascades known to be involved in the disease. Michael and his team have previously identified several areas (loci) in the human genome which are associated with acne.

They now want to study these areas in further detail to better understand the causal molecular and cellular events that lead to acne and hopefully identify targets for treatment. They will use a three-step approach. Firstly, by identifying the genetic variants linked to the disease by analyzing genetic data from more than 60,000 individuals with acne. Secondly, they will cross-link these variations to create a map of the signaling pathways and associated cells responsible. Finally, based on this mapping, they expect to be able to identify targets for future treatments of the disease. If successful, the results may provide the first steps towards a better and more targeted treatment for this very common and socially stigmatizing skin disease.

Investigating the regulation of Interleukin-36 cytokine activity in the pathogenesis of generalised pustular psoriasis

Grantee: Mark Mellett, Group Leader, University Hospital Zürich

Amount: DKK 2,055,914

Grant category: Research grants in open competition

Year: 2022

Geography: Switzerland

The overall aim of Mark Mellett’s project is to shed light on the differences and the mechanisms governing regulation of IL-36 activity in both skin inflammation and viral infection.

IL-36 cytokines (a substance secreted by cells that affect the response of nearby cells) are well-known to contribute to inflammatory skin diseases in particular generalised pustular psoriasis. Yet the mechanisms regulating the activitiy of the cytokines remain poorly understood.

Mark and his team suggest that IL-36 is an important response mechanism protecting the skin against viral infection and this response is “switched on” in error in generalised pustular psoriasis. They propose to elucidate the reasons for this to better understand how pustular psoriasis is triggered.

Molecular genetics of recalcitrant warts

Grantee: Hassan Vahidnezhad, Assistant Professor, Thomas Jefferson University

Amount: DKK 2,131,526

Grant category: Research grants in open competition

Year: 2022

Geography: USA

This project led by Hassan Vahidnezhad aims to elucidate the mechanisms behind skin warts that do not resolve automatically.

Warts are very common, approximately present in 20-35% of the general population. While they typically disappear within a few months, some linger and may be hard to get rid of. These persistent warts are caused by infection with Human Papilloma Virus (HPV) in persons where the immune response is insufficient due to genetic defects. Particularly, defects in T cells are suspected as a causation, but exactly how the warts are formed and how they persist is to a large degree unknown.

Hassan and his team seek to identify the genetic and molecular causes of recalcitrant warts, which will not only better the understanding of the skin’s immunological response to HPV infection, but may also provide diagnostic, prognostic and therapeutic improvements for patients with recalcitrant warts.