Explore our grantees and awardees

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 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.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

This project initiative by Richard Granstein extends research previously funded by the LEO Foundation into the role of calcitonin gene-related peptide (CGRP) in regulating skin immunity by acting on endothelial cells (ECs – the cell type which lines the interior wall of blood vessels) and aims to elaborate on this regulation by studying the potential involvement of non-skin located ECs.

Recent studies have defined a novel pathway by which CGRP can skew the outcome of an immune response away from one type of T-cell mediated immunity (Th1-type) and toward another type (Th17-type) through actions on ECs. This work was originally done in cell cultures but subsequent studies using mice specifically lacking functional CGRP receptors on ECs found that this pathway indeed operates in vivo. Immunization of these mice led to decreased generation of Th17-type T cells in regional lymph nodes, but increased generation of Th1-type helper T cells. In addition, these mice were found to have severely depressed contact hypersensitivity responses. It is not known if the reduction in contact hypersensitivity responses relates to the observed changes in T helper cell differentiation. These results suggest that it may be possible to therapeutically manipulate diseases involving Th17 mechanisms, such as psoriasis, and, perhaps, other hypersensitivity disorders affecting the skin.

Given these results, it will be important to know more about the physiology of this novel pathway. Preliminary data suggest that ECs not in the skin may be sufficient targets for CGRP to exert the effects seen on T helper cell responses. Richard’s project proposes experiments to 1) test the hypothesis that ECs within regional lymph nodes are sufficient for the T helper cell effect observed in vivo and 2) to further define the mechanisms by which contact hypersensitivity is reduced in mice lacking functional CGRP receptors on ECs. Ultimately, these studies may suggest novel new routes for therapies.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

Cutaneous T-cell lymphoma (CTCL), a cancer of white blood cells, can look like atopic dermatitis. This project from Larisa Geskin aims to develop and validate a screening test for patients with atopic dermatitis (AD) which will aid in identifying undiagnosed CTCL in these patients.

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are essential cytokines (i.e., signaling molecules released from cells to the environment in order to affect other cells), in the pathogenesis of AD. Targeting these cytokines with antibodies such as dupilumab or tralokinumab has proven to be highly effective for therapy of AD.

However, patients with AD may have an increased risk for lymphoma, especially CTCL. There are numerous reports of patients with AD who received dupilumab and later developed CTCL, lethal in some cases. Therefore, therapies targeting IL-4/IL-13 are currently contraindicated for patients with CTCL. However, differentiation between AD and CTCL is difficult because of similar manifestations in the skin and lack of specific markers (i.e., molecules that are uniquely present or expressed in a given condition) for these diseases.

In their preliminary studies Larisa and her team have screened the blood of patients with biopsy-confirmed CTCL and AD for 18 highly selected potential biomarkers using an efficient screening method. Of the 18 tested biomarkers, 9 demonstrated sensitivity and specificity potentially adequate to differentiate CTCL from benign dermatoses. These data serve as a proof of principle and justify further studies, as described in this proposed project, to test a broader set of biomarkers to find the most promising biomarker panel with the highest sensitivity and specificity to develop a simple, robust and inexpensive test, which may be widely accessible to all treating physicians before initiating therapy for AD.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

Jeffrey Cheng’s project aims to improve our understanding and discrimination of chronic atypical skin rashes which do not fit into well-defined clinical categories. Jeffrey along with his team will approach this by first mapping gene expression variations on a single cell level for a number of prototypical rash types. This will allow them to create a framework to identify variations that can discriminate between well characterized rash types, which each have different treatment regimens. While they have already done this for rashes with atopic dermatitis- and psoriasis-like features, this project will add information about rashes with features common to cutaneous sarcoidosis and lupus erythematosus. Based on these findings, Jeffrey aims to establish a more accessible approach to classify these rashes by assessing tissue samples for presence of disease-relevant proteins.

If successful, Jeffrey and his team will provide important guidance for optimal classification and subsequent treatment of otherwise indeterminant rashes.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

This project led by Hassan Vahidnezhad aims to elucidate the mechanisms behind skin warts that do not resolve automatically.

Warts are very common, approximately present in 20-35% of the general population. While they typically disappear within a few months, some linger and may be hard to get rid of. These persistent warts are caused by infection with Human Papilloma Virus (HPV) in persons where the immune response is insufficient due to genetic defects. Particularly, defects in T cells are suspected as a causation, but exactly how the warts are formed and how they persist is to a large degree unknown.

Hassan and his team seek to identify the genetic and molecular causes of recalcitrant warts, which will not only better the understanding of the skin’s immunological response to HPV infection, but may also provide diagnostic, prognostic and therapeutic improvements for patients with recalcitrant warts.

Grant category: Research Grants in open competition

Year: 2022

Geography: USA

This project led by Dr. Nathan Archer investigates the interplay between bacterial colonization and a specific immune cell, the eosinophil, in development of atopic dermatitis (AD).

AD is a very common skin disease, particularly amongst young people, and the associated healthcare costs in the U.S. alone are estimated at USD 5.2 billion. Thus, there is a strong incentive to better understand the disease to improve its treatment.

The cause of AD is still unclear, but one interesting observation is that a specific type of immune cell, the eosinophil, infiltrates the affected areas and correlates with disease severity. The role of these eosinophils in AD remains unknown, but initial observations by Dr. Archer and his team point to a link between skin colonization of a specific bacteria, Staphylococcus aureus, and the observed infiltration – which may lead to both inflammation and itch. This bacteria-immune cell interaction is unusual, and Dr. Archer and his team will investigate the observed interaction in detail, with an aim to provide novel therapeutic targets for the treatment of AD.