Grant geography: USA

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.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Joshua Moreau’s project investigates the potential role of B cells (antibody-producing immune cells) in the inflammatory skin disease, hidradenitis suppurativa to create a foundation for future therapeutic approaches.

Hidradenitis suppurativa (HS) is a painful skin disease characterized by highly inflamed lesions. While the causes of lesion progression are not well understood, this inflammation is often marked by accumulation of an immune cell subset called B cells. In certain contexts, B cells cause damage to the body and perpetuate inflammatory responses, however, for this to happen these cells need to undergo a process of maturation to become antibody-producing plasma cells. In this project, Joshua Moreau aims to understand if B cells accumulating in HS affected skin mature into disease perpetuating plasma cells.

To do this, Joshua Moreau and his team will utilize a technique called spatial transcriptomics technology that allows them to track B cell maturation across a skin sample. This, in turn, will allow them to determine if plasma cells originate at the site of inflammation in the skin.

Additionally, the team will explore avenues for blocking B cell maturation specifically within the skin using advanced human skin tissue culturing approaches.

Collectively, these experiments may provide currently missing insight into the disease-causing potential of B cells in HS and form a foundation for targeting them therapeutically.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

The project of Emma Guttman aims to develop an improved understanding of the molecular basis of chronic hand and foot eczema to guide future treatment approaches.

Chronic hand and foot eczema is a highly prevalent disorder, affecting up to 15% of the overall population, and represents an enormous socio-economic and psychosocial burden. The condition is often refractory to conventional treatments. In addition, chronic hand and foot eczema shows considerable inter- and intra-patient heterogeneity, further complicating treatment options.

Importantly, overall pathophysiological mechanisms are still only insufficiently understood, as skin biopsies from these areas are very difficult to obtain due to the location in which it may implicate local pain, wounds, and visible scars. Thus, better sampling methods are urgently needed.

Emma Guttman and her team propose to use tape stripping, a non-invasive method that targets the outermost layers of the skin, to collect lesional and non-lesional skin samples. Through a multi-omics approach, including transcriptomic (looking at gene expression) and multiplex proteomic methods (looking at active proteins), these samples will be used for improved molecular and genetic understanding of chronic hand and foot eczema. Their study will include samples from adult patients with different forms of chronic hand and foot eczema, stratified for specific locations, severity, and clinical subtypes. Results will be compared to matched healthy control individuals.

If successful, results obtained from Emma Guttman’s investigation may identify disease-causing factors specific for chronic hand eczema subsets and locations, that could guide future targeted treatment approaches in a more personalized or stratified manner.

Grant category: Research Grants in open competition

Year: 2023

Geography: USA

Charles (Chiwei) Xu’s project aims to investigate the molecular basis for cutaneous neuropathies (i.e., sensation of pain, numbness or fatigue caused by neural damage).

Mouse skin contains a dense network of nerve endings and is a good system to study interactions between the peripheral nervous system and barrier tissues in mammals. Intriguingly, axons (the elongated, signal-transducing sections) of sensory neurons are closely associated with hair follicle stem cells (HFSCs) in the skin, and Charles Xu has identified ligand-receptor pairs that mediate signaling between the two cell types. Specifically, he has identified the HFSC-derived parathyroid-hormone-like hormone (Pthlh) as a top candidate factor required for sensory innervation. Charles Xu has also established that Pthlh signals through the receptor Pth1r in sensory neurons. To further study crosstalk between HFSCs and sensory neurons, he has established a 3D co-culture system of these cells. Using that system, he aims to further characterize Pthlh-Pth1r signaling in the context of direct HFSC-sensory neuron interactions in vitro. He also aims to investigate the physiological relevance in an in vivo mouse model. In doing so, Charles Xu and his team aim to establish a versatile technical platform to study cutaneous neuropathies, which are common disorders where there is currently a lack of both mechanistic understanding and effective treatment.