Primary cilia: a novel target for skin fibrosis
Grantee: Maria Teves, Assistant Professor, Virginia Commonwealth University, USA
Amount: DKK 3,914,945
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Maria Teves’ project explores mechanisms behind formation of dermal fibrosis, which is a hallmark of several skin disorders, including systemic sclerosis (SSc). Despite the identification of various contributing factors, the precise molecular mechanisms underlying skin fibrosis in SSc remain poorly understood and there is no effective treatment. In order to uncover these mechanisms and develop new therapeutic strategies, the project focuses on primary cilia (PC), which are specialized solitary cellular organelles involved in molecular signaling. Recently, Maria Teves and her research group discovered links between altered PC to SSc pathophysiology, revealing significant alterations in PC and PC-associated gene expression in skin biopsies from SSc patients. Furthermore, it was found that profibrotic signaling can be triggered both in vivo and in vitro by the genetic ablation of PC-associated genes or by pharmacological agents that damage PC. Building on this critical evidence, the project will test the hypothesis that PC represent novel therapeutic targets for SSc skin fibrosis. A comprehensive approach is proposed to define molecular contributions of PC to the pathogenesis of skin fibrosis and assess the potential of PC-targeted therapies for mitigating fibrotic phenotypes.
Maria Teves’ experiments may lay the groundwork for advanced understanding and possibly treatment and future clinical advances for people suffering from fibrotic skin conditions.
Identifying new, molecularly-targeted treatments for rosacea
Grantee: Anand Ganesan, Professor, The Regents of the University of California Irvine, USA
Amount: DKK 4,000,000
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Anand Ganesan’s project explores the activation of the innate immune system in rosacea, a chronic skin condition which affects 5% of the world’s population. Rosacea skin has an increased number of blood vessels, which can be induced by the naturally occurring anti-microbial peptide cathelicidin, which is produced by keratinocytes in rosacea skin. While treatment targets and new pharmacotherapies for rosacea have been identified, this knowledge has not yet been translated into new rosacea therapies. RhoJ, a member of the CDC42 GTPase family, plays a critical role in angiogenesis (formation of new blood vessels) in skin and other organs, and RhoJ knockout mice have decreased number of blood vessels in the skin as compared to wild type animals. Anand Ganesan and the research group has discovered a new class of small molecules that inhibit CDC42 GTPase signaling, which prevents vessel accumulation in the skin and colon through a RhoJ-dependent mechanism and also blocks the vascularization of human organoids. Anand Ganesan’s project couples’ single cell and spatial transcriptomics approaches (i.e., analyses of how genes are expressed in individual cells as well as throughout a tissue) with advanced bioinformatics to identify vessel inducing signals in tissue. The research plan includes 1) coupling single cell and spatial transcriptomics with advanced bioinformatics to identify rosacea inducing signals; 2) quantifying vascular changes in rosacea in mice and human model systems; and 3) testing the efficacy of CDC42 inhibitors at blocking cathelicidin-induced angiogenesis.
The project aims to identify new drug targets and test the efficacy of new treatments for rosacea.
Determining the Impacts of Testosterone on S. aureus-induced Skin Damage in Atopic Dermatitis
Grantee: Tamia Harris-Tryon, Associate Professor, UT Southwestern Medical Center, USA
Amount: DKK 2,852,706
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Tamia Harris-Tryon’s study explores atopic dermatitis (AD) which affects seven percent of adults and twenty percent of children. AD has the highest impact on patient quality of life among skin disorders. The pathogenesis of AD is incompletely understood, and there is an increasing appreciation for the contributions of the microbiome. During AD flares, Staphylococcus aureus expands and exacerbates inflammatory responses and skin damage. While S. aureus dominates the skin microbiome in AD, the mechanisms that drive bacterial expansion during inflammation remain unclear. This question is important because skin breakdown in AD is aggravated by S. aureus toxins. S. aureus exotoxins have been shown to stimulate skin inflammation. Tamia Harris-Tryon’s project will test the central hypothesis that testosterone promotes S. aureus-induced skin damage and inflammation in AD as well as investigate how testosterone stimulates S. aureus-induced skin damage in culture and in mouse models. These experiments will also make use of genetically engineered mice with reduced testosterone production in the skin. This approach will reliably determine how testosterone regulates S. aureus-induced skin damage and inflammation.
The results of Tamia Harris-Tryon’s project may reliably determine how testosterone regulates S. aureus-induced skin damage and inflammation.
Viral hijacking of embryonic signaling pathways in trichodysplasia spinulosa
Grantee: Andrzej Dlugosz, Professor, University of Michigan, USA
Amount: DKK 3,985,000
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Andrzej Dlugosz’s project explores how a skin-associated virus called TSPyV can cause a striking hair follicle disorder called trichodysplasia spinulosa. In patients affected by this condition hair follicles on the face and ears are enlarged, structurally abnormal, filled with TSPyV viral particles, and produce spikes instead of hairs. To understand how TSPyV disrupts hair follicle biology Andrzej Dlugosz and his group created genetically engineered mice that express TSPyV viral proteins in skin. These mice produced enlarged and abnormal-appearing follicles and developed follicle-like structures in hairless areas, suggesting that TSPyV can somehow reprogram skin to drive growth of hair follicles which are needed for large-scale virus production. In keeping with this concept, one of the TSPyV viral proteins triggers abnormal activation of an important molecular signal that regulates formation and maturation of hair follicles. The studies will examine hair follicles in trichodysplasia spinulosa using powerful new molecular technologies to better understand the alterations in behavior and maturation of follicle cell types in this disease. They will also investigate how a specific TSPyV protein hijacks an important hair follicle signaling pathway, contributing to the profound changes seen in the skin of trichodysplasia spinulosa patients.
The results of the project have the potential to yield new insights into the regulation of molecular signals controlling formation and growth of hair follicles, based on findings from studying this rare condition.
Ex Vivo Culturing of the Human Skin Microbiome
Grantee: Beth McLellan, Professor, Albert Einstein College of Medicine, USA
Amount: DKK 4,054,452
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Beth McLellan’s project, in collaboration with co-PI and Kosaku Shinoda, explores the functional interactions of live or viable bacteria within the skin microbial community, and their implications in skin disease. The project aims to develop a robust ex vivo model, Skin Microbiome in a Test tube (SMT), to study the dynamic biochemical activity of the viable skin microbiome. Preliminary data indicate that the prototype version of the SMT system (v1) is capable of preserving the diversity of skin bacteria ex vivo. The aims are to (1) refine SMT using Propidium Monoazide (PMA) sequencing to exclusively replicate the viable microbiome and (2) investigate the impact of skin microenvironmental factors (e.g., moisture, sebum levels, and skin breakdown) on the composition and biochemical activity of the viable microbiome, using data from non-invasive sensors at multiple skin sites.
With the generation of the improved version of the SMT (v2), the project hopes to create an innovative platform for functional skin microbiome studies, drug screening and pharmacokinetic modeling with an emphasis on microbial viability leading to individualized treatment strategies based on microbiome community profiles. SMT will serve as a foundation for identifying biomarkers, developing microbiome-based therapies, and improving pharmacokinetic predictions.
Defining how skin microbial communities shape T cell function using a novel antigen-tracking technology
Grantee: Erin Chen, Assistant Professor, Broad Institute of MIT and Harvard, USA
Amount: DKK 3,929,293
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Erin Chen’s project aims to address the fundamental question: how do we translate the composition of our body’s colonizing microbes (our microbiome) into insight about immune function? Commensal bacteria (commonly known as just “commensals”) colonize our skin, over our entire lives, and generate the vast majority of microbe-host encounters, with largely unknown consequences. Erin Chen’s project focuses on commensals’ interactions with T cells because these cells critically impact many aspects of health and disease. Unlike infections, where a single pathogen invades into the tissue, commensals colonize within complex communities and communicate to the host immune system across an intact skin barrier. How the immune system decodes signals from each member of this community is unknown. Erin Chen and her team will address this by colonizing mice with defined communities of commensals and tracking the commensal-derived antigens along with the strain-specific T cells. To do this, they will develop novel methods to detect commensal-derived antigens within the host tissue, at high resolution. By varying the abundance and composition of community members, they aim to discover novel antagonistic, synergistic, and emergent properties of commensal-specific T cells. This work will provide visibility into a currently invisible process: how a lifetime of commensals on our skin are constantly sculpting our T cell function, which ultimately impacts our susceptibility to infections, autoimmunity, and cancer.
How innervation regulates regeneration and scarring responses
Grantee: Ya-Chieh Hsu, Professor, Harvard University
Amount: DKK 4,000,000
Grant category: Serendipity Grants
Year: 2024
Geography: USA
Ya-Chieh Hsu’s project investigates the mechanisms behind the unexpected observation that wound healing slows upon increased innervation of the surrounding tissue.
During testing of a virus-based tool designed to genetically manipulate skin cells Ya-Chieh Hsu and her team serendipitously discovered that increased innervation at a wound site slows healing and leads to increased scarring. This discovery suggests that wound-induced hyper-innervation may be important in driving scarring and fibrosis.
Dissecting the effects of sex hormones and sex chromosomes in heightened cutaneous inflammation in female mice
Grantee: Philip Scumpia, Associate Professor, The Regents of the University of California, Los Angeles
Amount: DKK 3,977,971
Grant category: Serendipity Grants
Year: 2024
Geography: USA
Philip Scumpia’s project will investigate a surprising discovery that links gender to differences in immune responses.
Philip Scumpia and his team created new formulations of biomaterials intended to improve cutaneous wound healing and decrease size of scars in his current LEO Foundation-funded project. While evaluating the immunological mechanisms, Philip and his team observed considerable variability in immune cell recruitment to the different hydrogels. After careful scrutiny they realized this variability was entirely due to the fact that female mice developed stronger immune responses to the hydrogel than male mice. Strikingly, female mice displayed a much earlier and more severe skin inflammation in other mouse models studied in the laboratory includingeczema, psoriasis, and sunburn.
Role for adipocytes and crosstalk with eosinophils in atopic dermatitis pathogenesis
Grantee: Nathan Archer, Assistant Professor, The Johns Hopkins University School of Medicine
Amount: DKK 3,999,693
Grant category: Serendipity Grants
Year: 2024
Geography: USA
Nathan Archer’s project investigates the surprising finding that dermal adipocytes and their crosstalk with eosinophils may play an important role in the development of atopic dermatitis.
The aim of Nathan Archer’s original project was to investigate the role of eosinophils, a type of immune cell, in the pronounced bacterial dysbiosis seen in relation to atopic dermatitis (AD). During those studies, Nathan Archer and his team serendipitously discovered an unexpected interaction of adipocytes with eosinophils in the skin, which was also associated with skin inflammation. This novel link will be investigated in Nathan’s project.
4th annual International Conference on the Science of Science and Innovation (ICSSI)
Grantee: Dashun Wang, Professor, Kellogg School of Management, Northwestern University
Amount: DKK 500,000
Grant category: Standalone grants
Year: 2024
Geography: USA
This interdisciplinary event will convene leading experts in the field of science of science and innovation, aiming to provide a multi-channel platform that brings together both producers (scientists from industry and academia) and consumers (policymakers, publishers, funders, administrators, etc.) of the field.