Explore our grantees and awardees

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

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Studies in human populations have identified dozens of pigmentation genes, many of which 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, there are other pigmentation genes that we know much less about, such as those that encode putative transporter proteins on the melanosome surface. These putative melanosomal transporters have been reported to import precursor metabolites for melanin synthesis or regulate melanosomal pH; however, many of these findings have been controversial or speculative. Deciphering the molecular function of these putative transporters and their physiological substrates is crucial to our understanding of pigmentation.

To address this problem, we propose to determine the metabolite composition of melanosomes and define the role of individual transporters in melanosomal function. We will develop a purification method to rapidly isolate intact melanosomes and analyse them by liquid chromatography and mass spectrometry to compile the first catalog of melanosomal metabolites. We will subsequently characterize SLC45A2, a putative melanosomal transporter that modulates human pigmentation in response to sunlight. By comparing the metabolite profile of wild-type versus SLC45A2-deficient melanosomes, we will identify candidate SLC45A2 substrates and validate them using biochemical assays, a workflow that will be applied to other putative melanosomal transporters.

This study will present the first detailed analysis of melanosome metabolites, as well as identify key metabolites and their transporters essential for melanogenesis. This work could inform new ways to modulate pigmentation and treat pigmentation pathologies.

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

We will develop a novel ionic-liquid formulation for topical delivery of nucleic acids into the skin.

Our ionic liquid enhances lipophilicity of nucleic acids by ~100,000,000 fold and enhances their penetration into the skin. We will demonstrate the feasibility of the platform through delivery and efficacy of two siRNAs. The resulting platform is expected to have broad applications to other nucleic acid drugs including mRNA for the treatment of a wide range of dermatological conditions.

Our ionic liquid platform will open new opportunities for the treatment of dermatological conditions.

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Melanoma is the deadliest form of skin cancer with few treatment options to patients with advanced metastatic disease.

Melanoma metastasis to lymph nodes is associated with expression of the chemokine receptor CCR7, a member of the G protein-coupled receptors (GPCRs) superfamily that promote cell migration of immune cells. Classically, upon agonist stimulation, GPCRs at the cell membrane activate heterotrimeric G proteins, causing downstream signaling throughout the cell. In order to terminate G protein signaling, cells have devised a specialized desensitization mechanism that includes receptor phosphorylation by GPCR kinases and subsequent recruitment of β-arrestins (βarrs) to the phosphorylated receptors. The GPCR–βarrs interaction both blocks the G proteinbinding site and promotes receptor endocytosis.

However, we recently discovered that some GPCRs interact with G proteins and βarrs simultaneously to form GPCR–G protein–βarr ‘megaplexes’, which allows the receptor to continue to stimulate G protein signaling while being internalized into endosomes by βarrs. Our preliminary results suggest that CCR7 forms megaplexes and promotes G protein signaling from internalized compartments. Interestingly, endosomal signaling, in general, is highly involved in cell migration, and different proteins are trafficked between plasma membrane and endosomes during this process. Thus, the proposed project aims to investigate the involvement of endosomal CCR7 signaling in melanoma cell migration. Furthermore, using a combination of highly advanced cryo-electron tomography and APEX2 proteomics, we will visualize the mechanism of CCR7-mediated melanoma cell migration protein-by-protein. Such detailed mechanistic knowledge will assist in designing innovative therapeutics to treat metastatic malignant melanoma.