Grant geography: USA

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.

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.

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.

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.

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.

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.

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.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Ralf Paus’ project aims to elucidate the role of the fragrance linalool in the development of frontal fibrosing alopecia (a type of involuntary hair loss).

Frontal fibrosing alopecia (FFA) is an ever more common, disfiguring inflammatory hair disease of primarily post-menopausal women. Since many FFA patients are allergic to fragrances like linalool, contained in 63-90% of personal care/household products, Ralf Paus and his team investigated whether this lead fragrance can promote core FFA pathogenesis events in human scalp hair follicles (HFs), which express “smell” (olfactory) receptors (ORs) for this fragrance, and indeed linalool induced overexpression of a key inflammatory “danger/distress” signal (MICA), reduced the pool of HF stem cells, and transformed some of them into fibroblasts (EMT).

Thus, Ralf Paus and his team hypothesize that linalool causes overexpression of MICA and excessive chemokine secretion by stimulating specific ORs; this attracts MICA-responsive immune cells that induce bulge immune privilege (an anatomical area relatively protected from inflammatory immune responses) collapse and stem cell death or EMT, leading to hair loss and scarring.

In Aim 1, they will probe this hypothesis in organ-cultured healthy human HFs, and non-lesional scalp skin of linalool-sensitized FFA patients. In Aim 2, they will dissect mechanistically by OR1A1 or OR1C1 silencing (i.e., preventing certain ORs from being expressed) which linalool-induced, FFA-promoting events depend on OR signaling.

If they can confirm that linalool can promote or even initiate core FFA pathogenesis events, namely in sensitized individuals, this will identify a novel immunological stem cell damage mechanism and could have major consumer protection and preventive medicine implications.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Patrick Brunner’s project aims to better understand the role of eosinophils, a type of granulocyte, in inflammatory skin diseases.

Granulocytes are key components of the innate immune system, that can react rapidly to various infectious agents and noxious stimuli. Despite their central role in host defense, their mechanistic relevance to human skin disease is still only insufficiently understood. Particularly eosinophils are prominently found in various inflammatory skin conditions associated with type 2 immune skewing (i.e., a response governed by T helper cells type 2 and a characteristic set of released cytokines, like IL-4 and IL-13). These include atopic dermatitis, bullous pemphigoid, hypereosinophilic syndrome (HES), urticaria, allergic reactions including DRESS (Drug reaction with eosinophilia and systemic symptoms), or parasitic infestations.

IL-5 is believed to be a key growth and differentiation factor for eosinophils. While IL-5 blockade is effective in e.g., HES, urticaria and DRESS, it is largely ineffective in atopic dermatitis or bullous pemphigoid, suggesting substantial functional eosinophil heterogeneity across these conditions. However, underlying mechanisms remain entirely unexplored, due to the difficulty in isolating and propagating these cells.

By using novel high-throughput analysis techniques such as single-cell RNA sequencing (scRNAseq) and spatial transcriptomics, complemented by functional in vitro experiments, Patrick Brunner and his team want to characterize eosinophils from skin and blood of patients with classic type 2 diseases, and define their in-situ skin tissue niche (i.e., microenvironment).

With this study, they hope to better understand eosinophil heterogeneity across skin diseases, define yet unrecognized subtypes within the human immune system, and help to develop better future treatment approaches.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Shadmehr (Shawn) Demehri’s project aims to elucidate the potentially beneficial role of polyomavirus infections in lupus.

Lupus is a major autoimmune disease characterized by the immune system’s attack on the body’s tissues and organs. Lupus affects over 5 million individuals worldwide, with an estimated 16,000 new cases diagnosed annually in the United States alone. Chronic inflammation caused by lupus impacts the skin, kidneys, and brain. Despite significant progress in understanding the pathophysiology of autoimmune diseases, lupus patients continue to experience substantial morbidity affecting their quality of life.

Polyomaviruses are small DNA viruses that are commonly found in nature. In immunocompetent individuals, polyomaviruses persist at low levels in the host after the primary infection, usually without causing any noticeable symptoms. Clinical research suggests that lupus patients with polyomavirus DNA in their urine may exhibit reduced kidney inflammation and lupus antibodies.

These clinical observations, together with preliminary findings by Shawn Demehri and his team, suggest a potential protective role for commensal (i.e., naturally occurring and non-pathogenic) polyomaviruses in lupus. To investigate the role of polyomavirus as a novel lupus therapy, the group aims to: (a) elucidate the mechanisms by which polyomavirus suppresses inflammation, (b) examine the impact of polyomavirus on lupus development, and (c) determine the potential of polyomavirus to enhance the therapeutic effects of current lupus treatments.

By exploring these avenues, they hope to uncover new insights into the potential use of polyomavirus as a therapeutic strategy for lupus.