Immunomodulatory porous biomaterials for skin regeneration

Grantee: Philip Scumpia, Assistant Professor, University of California – Los Angeles, CA

Amount: DKK 3,885,333

Grant category: Research grants in open competition

Year: 2021

Geography: USA

This project predicts in situ/local immunomodulatory biomaterials as a novel therapeutic approach to engineer regenerative wound healing and limit scarring.

Local tissue engineering represents a promising approach to regenerate tissue, however, immunologic barriers to restore tissue strength and function must be overcome. In previous studies, Philip Scumpia has shown that by simply inducing an adaptive immune response from a novel synthetic biomaterial that mimics the natural porosity and other characteristics of the skin, it is possible to provide the inductive signals to regenerate hair follicles and sebaceous glands in small murine cutaneous wounds.

In this project, it is proposed to identify the cells and the signals from the innate and adaptive immune system responsible for switching profibrotic signals in the wound environment to regenerative signals. This will be achieved by combining novel, pro-regenerative biomaterial formulations with loss-of-function studies of cells and factors of the immune system. Single-cell RNA-sequencing, multiplexed immunofluorescent microscopy, and bioinformatics analyses will be applied to directly assess biomaterial-to-cell and cell-to-cell interactions at the molecular level.

If successful, the project may help identify key players in regenerative wound healing, which would be of great importance.

Sodium intake and storage in the skin

Grantee: Katrina Abuabara, Associate Professor, University of California – San Francisco, CA

Amount: DKK 3,965,534

Grant category: Research grants in open competition

Year: 2021

Geography: USA

The rapid increase in prevalence of AD suggests that environmental factors play an important role, but which environmental drivers are most important and the mechanism by which they impact AD is unclear. Large epidemiological studies suggest that changing diets are an important contributor. Dietary sodium intake warrants additional investigation because studies have shown high rates of sodium storage in the skin and that high sodium concentrations can trigger inflammatory responses involved in AD.

To study this, Katrina Abuabara will enroll 30 participants and employ a novel Magnetic Resonance Imaging (MRI) technique that has been shown to accurately quantify skin sodium concentration to examine whether a low-sodium diet can decrease skin sodium concentration and improve AD severity. The study presents a strong statistical analysis plan to identify key parameters for a future full-scale clinical trial.

If sodium restriction proves to be beneficial, it could lead to actionable impact on AD patients as a cost-effective, low-risk intervention that could be implemented in low resource settings.

Regeneration of new fat cells in skin wounds from epigenetically plastic myofibroblasts

Grantee: Maksim Plikus, Professor, University of California – Irvine

Amount: DKK 3,923,850

Grant category: Research grants in open competition

Year: 2021

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.

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

Summary available soon.

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.

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.

Role of Skin Stem Cells in Psoriasis and Atopic Dermatitis

Grantee: George Murphy, Professor, Brigham & Women’s Hospital, Boston

Amount: DKK 3,988,427

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.