The LEO Foundation Award 2024 – Region Americas

Grantee: Shruti Naik, Associate Professor, NYU Langone Health

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2024

Geography: USA

Dr. Shruti Naik is Associate Professor at the Ronald O Perelman Department of Dermatology, NYU Langone Health, in the US.

She receives the award in recognition of her exceptional scientific achievements, clear long-term career objectives, and innovative vision for skin research – which delves into the complex interactions between immune cells, surrounding skin cells, and skin-dwelling microbes to understand the origins and progression of skin diseases.

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SID Future Leaders Retreat

Grantee: Society for Investigative Dermatology

Amount: EUR 25,000

Grant category: Research Networking

Year: 2024

Geography: USA

The Future Leaders Retreat (previously known as Resident and Post Doc Retreat) is a conference hosted by the Society for Investigative Dermatology (SID) each year since 2001. The program format provides a protected space in which residents can interact with senior faculty and established investigators for the purpose of fostering attendee’s interest in academic research careers. The program is a combination of formal lectures and presentation, informal discussions, brainstorming sessions and social activities. The Retreat is held at the time of the SID annual meeting, which allows attendees to establish connections with each other, and to other meeting attendees. These social networks foster collegiality, collaborations, an appreciation for the creative, multidisciplinary nature of science and other productive interactions. Sustained exposure to the entire spectrum of dermatologic research will influence the trainees as they make their career decision, as well as build their enthusiasm for this area of science.

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Epigenetic regulation of sebaceous gland development and homeostasis

Grantee: Brian Capell, Assistant Professor, University of Pennsylvania

Amount: DKK 2,885,457

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Brian Capell’s project seeks to better understand how epigenetic changes (modifications that do not change the sequence of genomic DNA) regulate the development of sebaceous glands.

Dysfunction of sebaceous glands (SGs) has been linked to a variety of common skin disorders ranging from atopic dermatitis to acne, sebaceous hyperplasia, seborrheic dermatitis and sebaceous tumors.

Brian Capell and his team have recently discovered that through genetic modification of the epigenome, they could promote a dramatic increase in the number and size of SGs (Ko, et al. Developmental Cell. In press. 2024). This surprising result demonstrated the direct role that epigenetics and chromatin organization plays in controlling SG development and abundance. It also suggested that targeting the epigenome might offer new ways to treat disorders characterized by aberrant SG development and activity.

Diseases related to aberrant SG development or activity can have a deleterious effect on both human physical and mental health. Despite this, very little is known of the role of epigenetics in SG development and homeostasis. To address this, Brian Capell’s project aims to test the influence of epigenomic modifiers and modifications upon SG development and disease to further dissect their contribution to the pathogenesis of these very common conditions.

Collectively, this project will address outstanding questions regarding the role of the epigenome in SG development and homeostasis and in common diseases driven by SG dysfunction – diseases that are both understudied and in need of better therapies.

Endothelial senescence in the pathogenesis of systemic sclerosis

Grantee: Eliza Pei-Suen Tsou, Assistant Professor, University of Michigan

Amount: DKK 3,990,092

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

The goal of Eliza Pei-Suen Tsou’s project is to understand the importance of aging endothelial cells (a cell type lining blood vessels) in scleroderma.

Scleroderma is an autoimmune disease characterized by inflammation, scarring of tissues and organs, including the skin, and changes in blood vessels throughout the body.

Most patients experience vascular abnormalities as one of the first symptoms, which trigger tissue stiffness and related complications later in the disease. Although these vascular changes are early critical events, the underlying cause of why they occur has not been determined.

Eliza Pei-Suen Tsou and her team found that dermal endothelial cells from scleroderma patients function differently compared to healthy controls. In particular, these cells undergo senescence, which is a process by which a cell ages but does not die off when it should. Over time, large numbers of senescent cells build up in the body. These cells remain active and release harmful substances that may cause inflammation and damage to nearby healthy cells.

In this project, Eliza and the team aim to determine the cause for vascular abnormalities in scleroderma, with a specific focus on how senescence is involved. They hypothesize that endothelial cell senescence is fundamental in causing the disease and might be targeted for therapy. Specifically, they propose that endothelial senescence accounts for the abnormality of endothelial cells in scleroderma, resulting not only in blood vessel changes but also in tissue scarring.

The goal is to determine why the endothelial cells acquire the senescent phenotype, and what this senescent phenotype does to promote the disease.

This project may form the basis for novel approaches to treating scleroderma.

Understanding structural and functional differences between JAK family JH1 and JH2 domains

Grantee: Christopher Bunick, Associate Professor, Yale University

Amount: DKK 4,165,955

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Christopher Bunick’s project aims to improve and substantiate our current knowledge of the structure and function of Janus kinases (JAKs) to improve safety and efficacy when developing new JAK inhibitors.

Janus kinase (JAK) inhibitors are small molecule drugs that treat inflammatory dermatological conditions by inhibiting cytokine signaling. Currently targeted diseases include atopic dermatitis, psoriasis, hand eczema, alopecia areata, vitiligo, and hidradenitis suppurativa.

Optimal JAK inhibitor matching to dermatologic disease remains challenging because of cross reactivity among four related JAK kinases: JAK1, JAK2, JAK3 and TYK2. Each possesses catalytic kinase (JH1) and allosteric (JH2) domains (an allosteric domain is a site where binding of a molecule indirectly modulates the function of the protein, here the catalytic activity). Both JH1 and JH2 domains have been targeted for drug development, yet a scientific knowledge gap exists as to how the allosteric JH2 domain regulates catalytic JH1 function and the subsequent downstream activation of signal transducer and activator of transcription (STAT) proteins.

A barrier for JAK inhibitor prescription is its promiscuity; it may target more than one JAK, leading to broader cytokine suppression than desired. This poor selectivity is likely rooted in suboptimal drug discovery procedures emphasizing inhibitory capacity over selectivity, resulting in unexpected real-world side effects, including malignancy, cardiovascular events, and thrombosis.

Christopher Bunick and his team will use AI-based generative modeling, molecular dynamics, computational biophysics, structural biology, and biochemistry to (i) determine how JH2 allosterically regulates JH1; (ii) define the structural basis for enhancing selectivity against specific JAK domains; (iii) elucidate downstream mechanisms regulating STAT signaling; and (iv) elucidate molecular properties of JAKs beyond JH1/JH2 domains.

This project may pave the way for better and safer treatment of skin diseases using JAK inhibitors.

Skin microbiome-metabolome modulation of skin homeostasis

Grantee: Julia Oh, Associate Professor, The Jackson Laboratory

Amount: DKK 3,953,521

Grant category: Research Grants in open competition

Year: 2024

Geography: USA

Julia Oh’s project aims to develop a novel and more physiological approach to studying how microbes interact with human skin cells and the effects of this interaction on overall skin health.

The human skin microbiome – encompassing hundreds of bacterial and fungal species – has essential roles in maintaining skin health. Skin microbiome dysfunction can contribute to diverse skin infections, inflammatory disorders, and skin cancer.

It is important to both identify the microbe–skin cell interactions that go awry in skin disease and to evaluate the therapeutic potential of new approaches for treating skin diseases. However, a detailed mechanistic understanding of how various skin microbes interact with human cells to maintain skin health or promote skin disease is currently lacking.

The goal of Julia Oh’s project is to determine how diverse skin microbes impact the essential functions of skin cells. However, there are few experimental models that allow us to investigate the diversity of skin microbes in a physiologically relevant way.

To enable a detailed investigation of microbe–skin cell interactions and their effects on skin health, Julia Oh and her team will model microbial colonization in cultured skin tissue that is genetically modified to investigate skin cell mechanisms. Then, using metabolomics and computational models, they will identify microbial metabolites to reveal microbial mechanisms.

This new approach could broadly enable biomedical researchers to determine how microbe–skin cell interactions impact skin functions, immunity, and susceptibility to diseases arising from microbial infection, and inform potential preventative and therapeutic strategies that harness the microbiome.

Investigate the onset of pathological remodeling events in SSc and assess their contribution to disease pathogenesis

Grantee: Valentina Greco, Professor, Yale University

Amount: DKK 3,818,950

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Valentina Greco’s project investigates the potential role of fibroblast and blood vessel maturation processes in systemic sclerosis (SSc) by monitoring development longitudinally in-vivo.

The skin protects organisms from their environment; it prevents water loss and infection and blocks physical insults. This barrier includes an outer layer and an inner, highly organized scaffold of fibers and blood vessels. Proper development of these two networks following birth is essential for health during adulthood; however, these processes are poorly understood.

Defects in the assembly and function of dermal fiber and blood vessel networks lead to severe diseases such as Systemic Sclerosis (SSc) or scleroderma. Identification of early SSc stages is crucial for the development of diagnostic, preventive, and therapeutic strategies. However, gaining this knowledge has been challenged by the inability to track these events longitudinally and in vivo.

Valentina Greco’s lab has overcome this roadblock and developed the ability for continuous visualization of skin networks, specifically how fibroblast and blood vessel networks develop after birth under healthy conditions. In this project – and building on this knowledge – they will utilize mouse models that mimic SSc in humans to investigate whether mechanisms crucial for postnatal skin maturation participate in this disease.

Valentina Greco’s project, if successful, will advance the understanding of the skin’s structural and blood vessel networks, shed light on their role in health and disease, and provide a solid foundation to improve clinical management of those suffering from often-lethal ailments such as scleroderma.

Modeling Hailey-Hailey disease to delineate its pathogenesis and identify therapeutic strategies

Grantee: Cory Simpson, Assistant Professor, University of Washington

Amount: DKK 4,054,629

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Cory Simpson’s project aims to investigate how mutations in the gene encoding the calcium pump SPCA1 cause the skin blistering disease Hailey-Hailey Disease (HHD) using human cellular and tissue models.

The epidermis forms the body’s outer armor from multiple layers of cells called keratinocytes, which assemble strong connections (desmosomes) to seal the skin tissue and prevent wounds. Several rare blistering disorders are linked to autoantibodies or gene mutations that disrupt desmosomes, causing keratinocyte splitting and skin breakdown. While autoimmune blistering diseases can be controlled by suppressing the immune system, treatments remain elusive for inherited blistering diseases.

One of these is Hailey-Hailey disease (HHD), which causes recurrent wounds, pain, and infections, leading to stigmatization of patients. Mutations in the ATP2C1 gene, which encodes the calcium pump SPCA1, were linked to HHD more than 20 years ago, yet the disease still lacks any approved therapies.

While it is known that SPCA1 resides in the Golgi apparatus (an organelle inside the cell responsible for protein processing and trafficking), our limited understanding of how SPCA1 deficiency compromises skin integrity has stalled drug development for HHD; moreover, mice engineered to lack SPCA1 did not replicate HHD.

Cory Simpson and his team at the University of Washington have built human cellular and tissue models of HHD to define what drives the disease and to discover new treatments. Their preliminary analysis of ATP2C1 mutant keratinocytes revealed impaired expression and trafficking of adhesive proteins, but also identified stress signals from mis-folded proteins and reactive oxygen species.

In this project, Cory Simpson and team will determine how these cellular dysfunctions compromise keratinocyte cohesion to cause skin blistering and test if cell stress pathways could serve as therapeutic targets for HHD.

Programming dermal fibroblasts to stimulate hair follicle regeneration

Grantee: Peggy Myung, Associate Professor, Yale University

Amount: DKK 2,135,432

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Peggy Myung’s project aims to elucidate how two key molecular signals regulate the development of dermal condensate cells, a group of cells pivotal for hair formation.

The hair follicle dermal condensate (DC) is a cluster of quiescent dermal cells that can induce new hair follicle formation and holds the potential to revolutionize hair loss treatments. However, a key barrier to exploiting DCs to make new hair is that the molecular and cellular mechanisms that lead to DC formation are poorly understood.

Peggy Myung and her team recently identified two morphogen signals that are necessary and sufficient to drive DC formation. These two signals cooperate to unfold an initial stage of progenitor proliferation followed by a stage of cell cycle exit and DC maturation. Importantly, these stages of differentiation depend on levels of these two signals: Low levels induce progenitor proliferation; higher levels induce quiescence and DC maturation.

They hypothesize that different signaling levels regulate these stages of differentiation by inducing distinct signature genes that cause either DC progenitor expansion or terminal differentiation. They recently established a high-throughput dermal culture system to test this hypothesis. Using this novel platform and in vivo hair reconstitution assays, they aim to define how modulation of levels of these two signals regulates dermal gene expression profiles, cell cycle dynamics and DC function.

If successful, Peggy Myung’s project may define tunable molecular targets to develop novel treatments for hair loss and to make DC organoids for drug testing.

Microbial impact on vitiligo development

Grantee: Caroline Le Poole, Professor, Northwestern University

Amount: DKK 2,979,828

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Caroline Le Poole’s project aims to investigate the potential link between the gut microbiome composition and vitiligo development.

The etiology of vitiligo involves a complex hereditary component, as well as environmental factors that precipitate disease. Caroline Le Poole and her team initially asked whether the gut microbiome impacts T cell-mediated autoimmune depigmentation. Manipulating the gut microbiome by oral antibiotics, they demonstrated a significant impact on vitiligo development in an established mouse model of the disease. Specifically, when using ampicillin to favor gut colonization by Pseudomonas species, they observed accelerated vitiligo development. Meanwhile, neomycin treatment was associated with an abundance of Bacteroides species in the gut, while mice in this group did not develop measurable depigmentation. These and other findings suggest that specific microbes can influence vitiligo development.

Here, they will test the hypothesis that the microbiome is a causative pathogenic factor fueling the autoimmune response to melanocytes causing the hallmark progressive depigmentation seen in vitiligo. The team will use mouse and human fecal transplants and manipulate the diet of vitiligo-prone mice. Moreover, individual microbial species will be introduced into germ-free mice before assessing depigmentation kinetics. Ultimately, therapeutic benefit may be derived from promoting the species that support regulatory T cell activity.