Explore our grantees and awardees

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.

Grant category: Research Networking

Year: 2023

Geography: USA

The Barrier Function of Mammalian Skin conference theme is “An Intelligent and Personalized Skin Barrier: Integration and Translation of Cell and Molecular Biology, Bioengineering and Physical Chemistry”. Keynote sessions include presentations on topics such as “Inflammation in Barrier Function and Dysfunction”, “Big Data to Knowledge: Models, Diagnostics and Therapies” and “The “Next Big Question on the Skin Barrier”. 

The Gordon Research Conferences are renowned for their excellent scientific programs and are unique in that each conferee agrees that any information presented at a Gordon Research Conference or Gordon Research Seminar, whether in a formal talk, poster session, or discussion, is a private communication from the individual making the contribution and is presented with the restriction that such information is not for public use. 

Grant category: Research Networking

Year: 2023

Geography: USA

The Montagna Symposia on the Biology of Skin are a very well-established conference, similar to a Gorden Conference, bridging the gap between basic research and dermatology. The meeting brings together scientists and physicians from academics to industry to foster interdisciplinary communication and collaboration in basic, translational and clinical research and practice, facilitating development of new collaborations, research and therapies for cancer, inflammatory diseases and other skin conditions. It provides a venue for the participation of high-profile, established speakers and up-and-coming stars in skin disease research and dermatology practice from around the world. The meeting facilitates the coming together of established researchers and clinicians with residents, fellows, and students; and representatives from government, foundations, and industry in a variety of fields and specialties, fostering the cross-pollination of ideas that is at the heart of breakthroughs in translational dermatology. 

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Macrophages, especially anti-inflammatory macrophages, are essential biological players in the process of dermal wound healing. However, maintaining an M2 phenotype within the inflamed wound microenvironment is quite challenging due to secretion of inflammatory cytokines from the wound. To overcome this limitation, Samir Mitragotri and his team have invented polymer micro-disks (“backpacks”) that carry potent anti-inflammatory agents. These “backpacks” are uniquely designed to possess a discoidal shape which keeps them attached to the monocyte/macrophage surface without them being taken up by the cell, and ensures continuous delivery of the anti-inflammatory agents to the cell carrying the backpack without elevating systemic drug concentrations. The project aims to develop a protocol to deliver such “backpack”-laden monocytes only once into the wound, where they can differentiate into macrophages and maintain themselves in the anti-inflammatory phenotype for an adequate time period to induce wound healing. The “backpack” technology has been pioneered by Samir Mitragotri and his lab. This novel strategy appears to have a unique advantage to control macrophage phenotype only for a pre-determined time, thus representing a promising new approach to dermal wound healing treatment.