Explore our grantees and awardees

Grant category: Research Grants in open competition

Year: 2020

Geography: USA

The aim of this project is to study regeneration of new skin, complete with hair follicles, glands and adipose (fat) tissue.

Maksim Plikus will use a mouse model where many new hair follicles and adipocytes (fat cells) are formed from the center of large skin wounds. It is known that at the center of large wounds, there are cells (called myofibroblasts) that are essential for wound healing – and that these cells can ‘re-program’ into fat cells which are essential for scarless wound healing. This capacity to change is lost at the edges of large wounds and in smaller wounds.

The re-programming will be investigated by looking into how the myofibroblasts change during wound healing and identify the source of the fat cell growth factors responsible for the change. The findings will be used to better understand why these changes do not take place at wound edges but start from the wound center.

If successful, the project may pioneer a new research direction on regenerative wound healing and inspire new therapeutic approaches to scarring.

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.  

Grant category: Research Grants in open competition

Year: 2020

Geography: USA

Summary available soon.

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.

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.

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.

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: 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.

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Many common skin infections are caused by the Gram-positive bacterial species Staphylococcus aureus and Streptococcus pyogenes. The infections lead to conditions ranging in severity from minor folliculitis to life threatening skin reactions. If not managed successfully, they may escalate into lethal systemic infections.

Commonly, these diseases are treated with clindamycin, a prototypical member of the wide-ranging so-called lincosamide antibiotic class. Its clinical importance is underlined by the World Health Organization’s listing of it as an essential medicine. In the past decades, however, prevalence of in particular lincosamide resistant Staphylococci and Streptococci has risen sharply. The rise threatens to diminish clindamycin’s usability in the future, even render it obsolete.

In the course of this project, the team led by Andrew G. Myers of Havard University, will seek to address this growing unmet medical need by synthetic discovery efforts focused on the lincosamide class.

The team’s preliminary results indicate that new lincosamides uncovered in this fashion are able to address the contemporary resistance threats: Many of the compounds designed, synthesised, and evaluated by the team to date have shown themselves active against multidrug-resistant clinical isolates of Staphylococci and Streptococci, and at the same time they demonstrate favourable pharmacokinetic and safety profiles.

The team expects that it can uncover new candidates displaying expanded spectra of action against MDR and Gram-negative bacteria. The expected results can then be used to advance refined lead candidates capable of demonstrating efficacy in in vivo murine models of skin infection, and thus yield substantial promise for further clinical development of actual treatments.

Project group

Dr. Amarnath Pisipati, Postdoctoral microbiologist

Matthew J. Mitcheltree, PhD student, chemistry

Ioana Moga, PhD student, chemistry

Katherine J. Silvestre, PhD student, chemistry

International affiliation

The Institut Pasteur, Annecy, France – International Course on Antibiotics and Resistance (ICARe), Organizing Committee, Core Faculty

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Two major challenges when using mouse models to model human cancers such as melanoma are that the human tumor cells transplanted to mice 1) represent the end-stage of the disease and 2) that the host animals are usually immunocompromised.

Thus, these models fail to actually show development of the disease and they fail to display the ongoing interaction between melanoma cells and the immune system as the disease progresses.

To curb these two shortcomings, the team led by Rudolf Jaenisch of Massachusetts Institute of Technology, has set out to create an experimental model system that will make it possible to study initiation, progression, and manifestation of human melanoma in immune competent host animals.

Their basis is generation of human-mouse neural crest chimeras – where mice embryos are introduced with human neural crest cells carrying the genetic dispositions alleged to lead to development of the particular cancer – and their goal is a model that has the potential to show how melanoma cells evade the immune system.

Given a positive outcome, this innovative project can help devise strategies to improve the effectiveness of current immunotherapies, to test novel immunotherapies, and to identify novel targets in melanoma treatment.

Project group

Malkiel Cohen, Postdoctoral researcher

Kristin Andrykovich, Graduate Assistant