Explore our grantees and awardees

Grant category: Research Grants in open competition

Year: 2019

Geography: Spain

Targeting ZEB1 in macrophages as a new therapeutic approach to psoriasis.

Psoriasis involves deregulation of the innate and adaptive immunities. The metabolism of T cells as well as of keratinocytes is altered in psoriasis. Metabolism also controls the immunogenic versus tolerogenic responses of macrophages through mechanisms still not fully understood.

Our preliminary data indicate that: 1) the transcription factor ZEB1 is downregulated in the skin of psoriatic patients and of mouse models of psoriasis as well as in the peripheral blood monocytes/macrophages of psoriatic patients; 2) ZEB1 expression in macrophages ameliorates psoriatic lesions in mice; 3) Mechanistically, ZEB1 regulates macrophage tolerogenic responses in psoriasis by inhibiting mitochondrial activity and reducing pro-inflammatory cytokines and ROS.

The project will investigate: 1) the molecular mechanisms by which ZEB1 modulates macrophage response in psoriasis; 2) the expression, role, and mechanism of action in psoriasis of the related factor ZEB2, which has opposing roles to ZEB1 in other contexts; 3) ZEB factors in macrophages as therapeutic targets in psoriasis.

Implementing this project will be impactful as it will explore a new pathogenic mechanism and inform the design of safer and more targeted therapies to improve the quality of life of psoriatic patients. The proposal is innovative both conceptually—proposing unexpected immunoregulatory roles for ZEB1/2—and methodologically—using unique mouse models and bridging macrophage biology, gene regulation, and metabolism.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

Long-term topical application of steroids such as hydrocortisone have severe skin side effects. Here treatments lead to thinning of the outer layer of the skin, reduced production of natural moisturisers and an increased risk of skin ulceration.

We hypothesise that an increased understanding of how hydrocortisone exerts its effect on skin cells will help us understand why hydrocortisone treatment causes these adverse effects and also aid the development of treatments that can bypass these.

Here we propose to take advantage of exciting new methods we have developed, where we can measure how cells behave within the skin and thereby quantify exactly how hydrocortisone affects cell turnover. This analysis will be combined with detailed studies for how hydrocortisone function at the mechanistic level in order to identify potential new therapeutic targets. Such therapies could be used to help patients receiving long-term hydrocortisone treatment.

Grant category: Research Grants in open competition

Year: 2019

Geography: Denmark

This project focuses on development of 3D bio-printed physiologically accurate human skin, which has important applications both clinically and for research.

3D printed human skin can be used in pharmacological and cosmetic testing, disease modelling, basic skin biology research, but also it can potentially save lives by providing skin grafts for burn or accident victims.

However, the current 3D printed skin is frail and prone to rupturing and does not recapitulate the native tissue. By combining quantitative imaging of intracellular junctions and cytoskeletal components at the sub-cellular, cellular and tissue levels in a rapid in vivo model and human 3D skin cell culture with direct measurements of tissue stiffness, we will deliver the most detailed description yet of the mechanical regulation and barrier properties of the skin.

Next, we will determine how the mechanical properties of skin change upon application of physical stimuli and if we could imitate the mechanical response by molecular perturbations.

Finally, we will identify and verify novel molecular players that set the mechanical properties of skin by unbiased single-cell sequencing of fragile and elastic tissues.

These results will be used to develop artificial 3D skin which more accurately represent human skin than current models. This interdisciplinary proposal is a crucial step forward in entering an era where animal experiments and transplants are replaced by synthetic organs printed for patients on demand.

Grant category: Research Grants in open competition

Year: 2019

Geography: Sweden

Skin is the largest human organ and contains an intricate variety of cell types that assure tissue architecture and proper skin function, such as thermoregulation and hair growth.

An imbalance of cell types and/or molecular signalling often results in disease. Across the body, skin composition differs in thickness, hair growth, sebaceous and sweat gland density, microbiota exposure and disease susceptibility.

However, a molecular understanding of how cell types and genetic programs vary with skin regions, and molecular alterations in disease, is currently lacking.

Previously, my lab pioneered the use of single-cell RNA-seq (scRNA-seq) in mouse skin by generating a comprehensive molecular and spatial atlas of epithelial and mesenchymal cells during hair growth and rest (Joost et al. 2016; Joost et al. 2019). Building upon our expertise, we will molecularly dissect human skin, initially through a body map that spans various body sites of healthy donors, to identify cell types and sub types in human skin and also to investigate important cell type differences and alterations compared to mouse skin. Subsequently, the body map will be the foundation for molecular analyses of skin diseases, including immune-triggered psoriasis.

A carefully constructed and annotated human skin atlas, with spatial and molecular precision, would have enormous value for the scientific community and propel our molecular understanding of skin in health and disease.

Grant category: Research Grants in open competition

Year: 2019

Geography: United Kingdom

There is a sterile inflammatory response to needle challenge driven by recruitment of inflammatory monocytes to the skin in old humans. This inflammatory response negatively correlates with cutaneous immunity after injection of varicella zoster virus antigens into the skin. Inhibition of the inflammation associated with the injury response, with a p38-MAPkinase inhibitor, reduced inflammatory monocyte recruitment and significantly enhanced antigen-specific immunity.

The aim of this project is to understand how inflammation and inflammatory monocytes inhibit antigen-specific T cells in the skin of old human volunteers.

The following experimental questions will be addressed: 1) Which cells are responsible for the inflammatory response to needle injury and how does the interaction between the infiltrating monocytes and other inflammatory populations amplify the response? 2) How are the inflammatory monocytes recruited to the site of challenge in the skin? 3) How do the recruited monocytes inhibit antigen-specific immunity in vivo in the old? 4) Using biobanked skin biopsy samples before and after the same older subjects have been treated with Vitamin D, we will determine gene expression signatures of how this treatment enhances cutaneous antigen-specific immunity.

These investigations will identify ways to enhance the immunity of older humans to vaccination and also infection and malignancy.

Grant category: Research Grants in open competition

Year: 2019

Geography: USA

Dozens of genes are known to be involved in human pigmentation. Many of these genes encode proteins with well-understood functions, such as in melanocyte development, melanin biosynthesis, and the biogenesis and trafficking of specialized melanin-containing organelles called melanosomes.

Yet, we do not know the molecular function of a class of pigmentation genes encoding putative transport proteins that localize to the melanosome. Identifying their substrates would represent a significant advance in our understanding of how melanin synthesis is regulated and how variants in these genes result in differences in human pigmentation.

Based on a method we developed to rapidly and specifically isolate melanosomes, termed MelanoIP, we can capture melanosomes in minute time-scales such that their labile metabolic contents are preserved for quantitative analysis.

Using this technology, we have performed a comparative study of melanosomal metabolites from cells with several pigment genes disrupted, including the putative melanosomal transporter encoding genes Slc45a2, Oca2, and Mfsd12, which has revealed potential substrates. In this proposal, we will define the substrates of these transporters using MelanoIP, metabolite profiling, and organellar uptake screens.

We will also perform follow-up biochemical analysis of each transporter and its naturally occurring genetic variants. Our unique combination of rigorous approaches will inform our understanding of how melanosomal transporters regulate melanin synthesis, and uncover the molecular basis of how mutations in these melanosomaltransport genes lead to human pigment variation.

Knowledge gained from this study will inform the development of interventions for modulating pigmentation and treating pigmentation pathologies.

Grant category: Research Grants in open competition

Year: 2019

Geography: United Kingdom

Epithelial tissues, the environmental barriers of our bodies, are constantly exposed to cancer causing agents. As such carcinoma, the cancer of epithelial tissues, are the most common form of cancer accounting for 85% of all cancers and 78% of all cancer associated deaths.

Many carcinomas arise from a pre-cancerous transformation, known as intraepithelial neoplasia or field cancerisation (FC), within which multiple carcinoma can develop.

By studying skin FC in a mouse model of human papillomavirus 8 infection (K14-HPV8-CER), we have uncovered specific expansion of only the Lrig1 hair follicle junctional zone keratinocyte stem cells (HFJZKSC) driven by ΔNp63 expression, which is the basis for skin FC 1-3.

These findings raised two important fundamental questions:

1. How does HPV8 induce Lrig1 KSC expansion? The background for this proposal and ongoing work (Leo Foundation grant 2017, LF17070).
2. Are Lrig1 derived cells responsible for squamous cell carcinoma (SCC)? The basis for this Leo grant proposal.

The current Leo Foundation grant allowed us to identify E6 as the HPV8 protein responsible for Lrig1 KSC expansion through activation of the STAT3 intracellular signalling pathway.

Therefore, we are now positioned for a follow-on grant to determine whether Lrig1 derived cells are responsible for FC associated SCC. Herein we aim to:

1) confirm that Lrig1 HFJZKSC proliferation is responsible KSC expansion into the infundibulum and adjoining interfollicular epidermis

2) test the hypothesis that Lrig1 HFJZKSC progeny give rise to papilloma and SCC

3) determine whether STAT3 mediate HFJZKSC expansion occurs in human skin FC.

Grant category: Research Grants in open competition

Year: 2019

Geography: USA

This two-year proposal is based on the hypothesis that skin stem cells are critically involved in the pathogenesis of psoriasis and atopic dermatitis.

In previous work, the three principal investigators have identified a cytokeratin 15-expressing stem cell niche at the tips of epidermal rete ridges, discovered immunomodulatory dermal mesenchymal stem cells, and defined an epigenetic mark that regulates skin stem cell behavior.

During the past year that was funded by the LEO Foundation, we have provided data that supports epidermal stem cell participation in human and experimental psoriasis and begun to probe the genetic and epigenetic underpinnings of this phenomenon.

We now propose to advance these findings to determine mechanistic commonalities in stem cell behavior that may unify the pathogenesis of psoriasis and atopic dermatitis. Specifically, the proposal focuses on epidermal and dermal stem cells in the context of innovative experimental models, human biospecimens to test relevance, and epigenetic modifiers that may be transformative in normalizing stem cell aberrations responsible for the initiation and propagation of these two prevalent, pernicious, and potentially preventable skin diseases.