Genetic and Epigenetic Mechanisms of Steroid-Related Skin Inflammation
Grantee: Bryan Sun, Assistant Professor, University of California - San Diego
Amount: DKK 2,995,615
Grant category: Research grants in open competition
Year: 2020
Geography: USA
Steroids are a powerful class of medications that are widely used to treat inflammatory diseases. In most cases, steroids block an overactive immune response. However, in skin diseases such as rosacea and perioral dermatitis, the chronic use of steroids can lead to worsened inflammation. While these worsened cases are common, it is not understood why steroids worsen disease and make them even more difficult to treat.
Bryan Sun and his research group recently discovered that an important cytokine which is elevated in rosacea, known as CCL20, is paradoxically activated in the skin by steroids. CCL20 increases inflammation by recruiting lymphocytes and dendritic cells. They found that steroid molecules directly bind and activate the CCL20 gene, overcoming the usual suppressive effects of steroids on inflammation. Based on this finding, they hypothesize that in some skin conditions, steroids directly activate the expression of genes that cause inflammation.
The goal of this project is to systematically identify genetic and epigenetic steroid targets in skin cells. If successful, the results would allow identification of new therapeutic targets for rosacea and perioral dermatitis, and lead to valuable insight into other steroid-resistant inflammatory diseases.
The 2021 Gordon Research Conference on Epithelial Differentiation and Keratinization (GRC-EDK)
Grantee: Salvador Aznar Benitah, Professor, Institute for Research in Biomedicine in Barcelona
Amount: DKK 204,130
Grant category: Research grants in open competition
Year: 2020
Geography: Spain
The 2021 Gordon Research Conference (GRC) on Epithelial Differentiation and Keratinization is the premier international meeting in epithelial biology.
The GRCs are known to promote intense interactions among the participants – who are experts in the field of the conference, leading to new knowledge, career mentoring, collaborations, and advancing as well as strengthening the field of the conference. This Gordon Research Conference will advance cutting-edge research in skin biology, promote translation of key findings to clinical practice, and further the careers of early stage investigators to maintain the highest level of innovation of this field in the future.
The LEO Foundation has previously provided support for the two previous Gordon Research Conferences.
Understanding the importance of cIAPs as NF-κB molecular switches in psoriasis
Grantee: Vasileios Bekiaris, Associate Professor, Technical University of Denmark
Amount: DKK 2,815,499
Grant category: Research grants in open competition
Year: 2020
Geography: Denmark
Psoriasis is an inflammatory disease characterized by overproduction of tissue-damaging cytokines by immune cells and keratinocytes. Central cytokines in psoriasis are TNF (tumor necrosis factor) and IL-17 (interleukin 17), which are currently approved therapeutic drug targets. To improve current therapies targeted towards TNF and IL-17, it is important to better understand the biology of the two cytokines in relation to psoriasis.
The goal of this project is to confirm that two enzymes known as cIAPs (cellular inhibitors of apoptosis proteins) play a central role in psoriasis.
The two cIAPs are believed to modulate the response of the immune system and of keratinocytes to TNF in order to fine-tune IL-17 production. The project will investigate whether lack of the two cIAPs or their pharmacologic inhibition makes the immune response less pathogenic and reduces the pro-inflammatory nature of keratinocytes during psoriasis.
Systemic effects of atopic dermatitis: Dysregulated immune responses to the intestinal microbiota
Grantee: Jeppe Madura Larsen, Senior Researcher, Technical University of Denmark
Amount: DKK 4,349,062
Grant category: Research grants in open competition
Year: 2020
Geography: Denmark
Atopic Dermatitis (AD) is a common inflammatory skin disease affecting 15% of children and 3-5% of adults. AD is associated with the risk for developing co-morbidities such as other atopic diseases (food allergy, asthma, and rhinitis) and infections. Co-morbidities are believed to occur because of functional changes in the immune system of AD patients, however, it remains unknown how these changes are established. Emerging experimental studies suggest the existence of a skin-gut immune axis, but the role for the gut remains largely unexplored in AD.
The goal of this project is to determine if AD changes the bacterial microbiota composition and function in the gut, alters the intestinal and systemic immune system, and increases the risk for food allergy co-morbidity via oral sensitization. The project hypothesizes that AD drives dysregulated immune responses to the gut microbiota, which in turn changes the immune system giving rise to atopic co-morbidities and risk for infections. In other words, it is envisaged that AD patients become “allergic” to the bacteria present in their intestine – leading to a “persistent allergic reaction” due to continuous presence of bacteria in the intestine.
The project will use a rat model of AD to investigate the hypothesis and perform a human case-control study to support the clinical relevance of the findings. Identification of bacterial drivers of persistent type-2 inflammation could open new avenues for the prevention and treatment of AD and related co-morbidities.
Granzyme B: A novel therapeutic target in cutaneous leishmaniasis
Grantee: David Granville, Professor, University of British Columbia
Amount: DKK 2,023,506
Grant category: Research grants in open competition
Year: 2020
Geography: Canada
Cutaneous leishmaniasis (CL) is a designated ‘WHO top-neglected tropical disease’, with up to 1 million new cases worldwide annually. CL is an inflammatory skin disease caused by infection with Leishmania parasites that leads to tissue damage, ulcers, and severe scarring, despite current treatment options.
The goal of this project is to provide a key rationale for pursuing Granzyme B (GzmB) as a novel therapeutic target for the treatment of cutaneous leishmaniasis.
GzmB is a protein that is aberrantly elevated in CL lesions and other inflammatory skin conditions. GzmB activity has been demonstrated to cleave important proteins in the skin, thereby worsening tissue damage, delaying wound healing, and causing scarring in inflammatory patient skin specimens and in experimental models. Importantly, inhibition of GzmB has shown efficacy in delaying these disease phenotypes.
Using lesional specimens from CL patients, a well-established experimental model, and a GzmB inhibitor, the contributions of GzmB to inflammation, impaired wound healing, and scarring in CL will be delineated in this study.
Investigation of genetic variation and development of genetically defined cell models for Acne vulgaris therapeutic and cosmetic products evaluation
Grantee: George Church, Professor at Harvard Medical School, Harvard University and MIT, Cambridge, MA
Amount: DKK 3,926,475
Grant category: Research grants in open competition
Year: 2020
Geography: USA
Summary available soon.
Deciphering the functional role of circular RNAs in psoriasis
Grantee: Lasse Sommer Kristensen, Associate Professor, Department of Biomedicine, Aarhus University
Amount: DKK 2,467,477
Grant category: Research grants in open competition
Year: 2020
Geography: Denmark
This project aims to answer key questions related to a recently discovered new class of biomolecules, called circular RNAs. These RNA molecules appear to have an important role in early immune responses and the project aims to functionally characterize them in psoriasis patients and compare the results with data from healthy controls.
To study the RNA molecules, the project uses a combination of traditional molecular biology approaches and high-throughput technologies such as RNA-sequencing and NanoString technology.
In summary, this project aims to shed light on the distribution and functional relevance of circular RNAs within psoriatic plagues as well as in normal skin and potentially open new avenues for better treatment and management of psoriasis.
Atopic dermatitis in Sub-Saharan Africa: exploring immune phenotypes and mycobiome
Grantee: Marie-Charlotte Brüggen, Assistant Professor, University Hospital Zürich
Amount: DKK 1,886,076
Grant category: Research grants in open competition
Year: 2020
Geography: Switzerland
The goal of this project is to improve the understanding of atopic dermatitis (AD) in Sub-Saharan Africa by characterizing the immune responses and potential changes in the associated skin and gut mycobiome (the composition of fungi found in a defined area) in AD patients from a dermatological clinic in Moshi, Tanzania. Subsequently, the results will be compared with equivalent data from Central European AD patients to identify similarities and differences.
As previous studies in this area is practically non-existing, this study will be a first step towards understanding the immune phenotype of Sub-Saharan Africa AD and how environmental factors like the fungi of the skin and gut could influence it. This will be important with regard to future treatment options of AD in the region.
Molecular investigation of CCL5-hi chronic adult rashes (CCARs)
Grantee: Raymond Cho, Associate Professor, Dermatology, School of Medicine, University of California San Francisco, CA
Amount: DKK 3,330,056
Grant category: Research grants in open competition
Year: 2020
Geography: USA
Summary available soon.
Protein aggregation in host defense and skin inflammation
Grantee: Artur Schmidtchen, Professor, Dermatology and Venereology, Department of Clinical Sciences, Lund University
Amount: DKK 2,100,000
Grant category: Research grants in open competition
Year: 2020
Geography: Sweden
The primary goal of this project is to identify and characterize the ‘aggregatome’, which describes the complete and complex network of proteins that are involved in the specific mechanism where the body – via its immune system – protects itself e.g. from bacteria. Subsequently, the project will explore and define the roles of the ‘aggregatome’ in inflammatory skin diseases.
The ultimate goal is to obtain new and deeper understanding of diseases affected by protein aggregation and potentially identify biomarkers of diagnostic significance.