SID Resident and Post Doc Retreat
Grantee: Society for Investigative Dermatology
Amount: EUR 15,000
Grant category: Education and Awareness Grants
Year: 2020
Geography: USA
The SID mission is to advance the sciences relevant to skin disease through education, advocacy and scholarly exchange of scientific information.
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.
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.
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
This project aims to characterize a newly identified type of persistent rashes which resemble both eczema and psoriasis, but which differ at the molecular level.
Initial single-cell genetic screening of relevant immune cells from the rashes has identified a strong overlap in their genetic profile – especially in the expression of two specific cytokines, CCL5 and IL32 – cytokines are substances that are secreted by certain cells of the immune system and have an effect on other cells. At the same time, the classical markers of both atopic dermatitis and psoriasis are absent, suggesting that these rashes indeed may represent a novel condition.
The project aims to further identify and substantiate the genetic profiling by studying a larger patient population and link this to dupilumab treatment outcomes in order to stratify and optimize the treatment options available for this patient population.
Targeting Aberrant STAT3 Signaling in CTCL
Grantee: Sergei Koralov, Associate Professor, NYU Langone, NY
Amount: DKK 2,676,248
Grant category: Research Grants in open competition
Year: 2020
Geography: USA
The goal of this project is to elucidate the mechanism behind the beneficial effects of atovaquone, a well-tolerated anti-microbial drug, on the rare type of skin cancer – the T-cell lymphoma (CTCL). It is known that atovaquone inhibits malignant cells from growing and may induce cell death, but the precise mechanism(s) is not known.
Sergei Koralov and his team have previously developed an animal model of the CTCL disease and will use this along with cells from patients to investigate the effects of atovaquone. Specifically, they will look at how the drug affects the gene regulating protein STAT3 as hyperactivation of this has shown to be critically important in the development of cancerous T-cells.
Given the outstanding tolerability of atovaquone, it is believed that if its mode of action can be deciphered it may prove a powerful tool in the future for treatment of malignant and inflammatory diseases.
The LEO Foundation Award 2020 – Region Americas
Grantee: Dr. Ya-Chieh Hsu
Amount: USD 100,000
Grant category: LEO Foundation Awards
Year: 2020
Geography: USA
Ya-Chieh Hsu is the Alvin and Esta Star Associate Professor at the Department of Stem Cell and Regenerative Biology at Harvard University, Cambridge, USA.
Ya-Chieh Hsu receives the award in recognition of her research achievements in studying cell-cell interactions and how systemic changes in the body influence these interactions in the skin.
The LEO Foundation Award 2019 – Region Americas
Grantee: Maksim Plikus
Amount: USD 100,000
Grant category: LEO Foundation Awards
Year: 2019
Geography: USA
Maksim Plikus is Associate Professor at the Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, USA
He receives 100,000 USD for his research in skin stem cells and regeneration.
SID Resident Retreat for Future Academicians
Grantee: Society for Investigative Dermatology
Amount: EUR 15,000
Grant category: Education and Awareness Grants
Year: 2019
Geography: USA
The SID mission is to advance the sciences relevant to skin disease through education, advocacy and scholarly exchange of scientific information.
Elucidating the origins of melanoma
Grantee: A. Hunter Shain
Amount: DKK 2,500,000
Grant category: Research Grants in open competition
Year: 2019
Geography: USA
The overarching goal of this grant is to better understand the origins of melanomas that appear suddenly, or de novo.
Approximately 70% of melanomas appear in this way, while the remainder grow out of preexisting nevi. Nevi can be monitored and prophylactically removed if they show signs of change, but melanomas that arise de novo are impossible to foresee. It is therefore of utmost importance to understand the origins of melanomas that appear de novo in order to develop biomarkers to predict their emergence.
We previously sequenced melanomas adjacent to nevi, revealing two classes of mutations – initiating mutations (emerging in nevi) and progression mutations (emerging in melanoma). Here, we hypothesize that progression mutations can precede initiating mutations. In this scenario, a melanocyte silently accumulates progression-associated mutations, followed by an initiating mutation so that the ensuing neoplasm ‘skips’ the precursor stages, manifesting directly as a melanoma.
If validated, this hypothesis would explain how de novo melanomas evolve. Here, we will genotype individual melanocytes from healthy human skin to test whether morphologically normal melanocytes can harbour progression mutations. Towards this goal, we have developed innovative solutions to establish high-quality genotyping calls from individual cells. In our preliminary data, we genotyped 17 melanocytes collected from healthy skin, and pathogenic mutations were surprisingly common, supporting our hypothesis. We will extend these studies to fully delineate the spectrum of cancer-associated mutations in melanocytes from healthy skin.
Overall, completion of these studies will reveal the origins of melanomas that do not pass through a precursor stage – a longstanding goal in the skin research community.
A multi-pronged approach to decipher the role of melanosomal transporters in human pigmentation
Grantee: David M Sabatini, Professor of Biology, Whitehead Institute of Biomedical Research
Amount: DKK 2,666,588
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.