Grant category: Research Grants in open competition

Grant category: Research Grants in open competition

Year: 2024

Geography: Denmark

Eva Kummer’s project targets to improve our understanding of the replication machinery of the skin-infecting herpes simplex virus (HSV) in order to improve and expand treatment opportunities.

HSV is one of the most widespread viral infections. The virus persists lifelong in the nerve system of the host and causes recurrent infections with mild to severe symptoms.

Since decades, treatment of herpes infections has exclusively targeted the viral replicative DNA polymerase (an enzyme that copies the viral DNA) using nucleoside analogs. However, resistance to current nucleoside analogs is emerging necessitating the search for alternative targets.

A major caveat in developing anti-herpetic compounds is a lack of structural information of other components of the herpes simplex replication system, which are likely strong candidates for targeted drug development. Eva Kummer and her team will use cryo-electron microscopy to visualize the architecture and working principles of the protein complexes that drive herpes simplex replication. They will also aim to clarify how novel anti-herpetic drugs block the viral replication machinery and why naturally occurring resistance mutations inhibit their action.

Overall, the project will generate structural and functional insights of the HSV replication strategy and potentially improve and accelerate anti-viral drug design.

Grant category: Research Grants in open competition

Year: 2024

Geography: Austria

Georg Stary’s project aims to investigate interactions between T cells and structural cells, including keratinocytes, in the skin and how this cellular communication may affect the function of the T cells in dermatological diseases.

Human skin is protected by specialized T cells, called tissue-resident memory T cells (TRMs), which are needed to protect against infection at the site of pathogen encounter, but can also mediate inflammation in certain conditions. The exact regulation of TRMs in human skin is not well understood, hence TRM-targeted therapies are currently unavailable.

Georg Stary and his team have discovered that T cells communicate with structural cells of the skin via certain surface molecules and acquire a TRM phenotype after interaction with keratinocytes and fibroblasts. Some of the newly described molecules that instruct T cells to become TRM have not been implicated in the regulation of T cell tissue residency before.

Georg and his team aim to explore how structural cells of the skin instruct the maintenance of human TRM, and how this cellular crosstalk changes during inflammation. Based on preliminary data, they will unravel the function of certain co-receptors in TRM regulation using modern single-cell sequencing technologies on primary tissue from patients and ex-vivo co-culture systems with genetically engineered human cells. Based on this, they will subsequently test the therapeutic potential of targeting T cell-structural cell interactions in a humanized mouse model of TRM-mediated skin inflammation.

This study will not only inform about new mechanisms of human TRM instruction in health and disease and explore options for developing clinical applications targeting interactions with structural cells, but also form the basis for designing clinical studies to treat selected TRM-mediated diseases, such as graft-versus-host disease or psoriasis.

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: Netherlands

Renate van der Molen’s project will study the effect of psoriasis and the associated treatment with biologics on the pre-pregnancy uterine immune environment and also investigate the effect on trophoblast invasion using a co-culture cellular model.

Pregnancy in patients with immune-mediated diseases like psoriasis is challenging and requires a tightly regulated immune system. The mother’s immune system must prevent rejection of the fetus that partly represents paternal characteristics and thus foreign to the mother’s immune system, while still being alert to infections threatening herself and the baby. Additionally, the immune system is important for invasion of fetal cells (trophoblast cells), into the cell lining of the womb to form a healthy placenta. Thus, a dysregulated immune system, i.e., during flares of psoriasis, can negatively affect pregnancy.

Furthermore, knowledge of the effect of biologics to treat psoriasis, anti-TNFα, anti-interleukin-17 (IL17) and anti-IL23, on pregnancy is sparse. This complicates decision making on treatment of women with psoriasis before and during pregnancy.

In this project, Renate van der Molen and her team will therefore study the effect of psoriasis and the treatment with biologics on the local uterine immune environment. In addition, using an innovative in vitro co-culture model of trophoblasts and immune cells they will study the effect of psoriasis and the treatment with anti-TNFα, anti-IL17 or anti-IL23 on trophoblast invasion.

Renate van der Molen’s project will give insights to whether and how psoriasis and the treatment with biologics can affect a future pregnancy, which is a step towards better evidence based clinical decisions on the best treatment for women with psoriasis with a child wish.

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: United Kingdom

Sofia Ferreira Gonzalez’s project aims to characterize the regenerative capacity of the spiny mouse – the only mammal known to fully regenerate skin with minimal scarring – to optimize future wound treatment in humans.

Skin fibrosis is often a sequela of suboptimal wound healing following significant epidermal and/or dermal injury (burns, trauma, major surgeries). Fibrotic material replaces native skin with dense, non-functional connective tissue, ultimately leading to loss of function. In its mildest form, fibrosis is a minor aesthetic problem, but in the most severe cases it can lead to debilitating skin pathologies that result in limited movement, high morbidity, and prevention of patient reintegration into society.

Current treatments for fibrosis include physical therapy and surgery, but there are no therapies that directly target the underlying cellular and molecular mechanisms of skin fibrosis.

The spiny mouse (Acomys) is, to date, the only mammal capable of skin autotomy (i.e., self-amputation of the skin to elude a predator’s grasp). Fascinatingly, the spiny mouse completely regenerates the lost skin and regrows cartilage and appendages (nails, hair) with minimal fibrotic response.

A multimodal approach addressing the mechanisms driving spiny’s scarless regeneration may provide novel therapeutic opportunities to treat and prevent skin fibrosis.

In this project, Sofia Ferreira Gonzalez and her team investigate three questions: 1) is the spiny mouse’s scarless regeneration depending on specific cell populations, circulatory factors or a combination thereof, 2) which specific pathways are responsible for the scarless regeneration, and 3) how can the research findings be translated into novel therapeutics to improve skin wound healing in humans?

Grant category: Research Grants in open competition

Year: 2023

Geography: Austria

Adelheid Elbe-Bürger’s project investigates the pathogen:host interplay using ex-vivo skin models in relation to infections by Candida auris – a multidrug resistant fungus.

Drug-resistant microorganisms represent a serious human health threat worldwide. Candida auris (C. auris) is an emerging, multidrug-resistant human fungal pathogen. Its pronounced skin tropism (i.e., ability to infect) promotes persistent colonization of the skin and facilitates skin-skin transmission within health care facilities, leading to life-threatening infections of high mortality in immunocompromised patients.

The lack of clinically relevant primary human skin models with a disrupted barrier function has been a serious impediment to better understand the C. auris:host interplay during pathogenesis.

To counter this, Adelheid Elbe-Bürger and her team have developed unique, standardized human ex vivo skin models that allow them to study C. auris colonization and penetration as well as identify the immune cells that orchestrate both the recognition and immune defense against this fungus.

In Adelheid Elbe-Bürger’s project infected skin biopsies will be analyzed by single-cell RNA-sequencing, flow cytometry as well as confocal microscopy. Culture supernatants will be subjected to multiplex proteomics (i.e., a way to analyze many proteins simultaneously) to decipher host components governing fungal:host interactions.

The overarching aim is that the results will advance the understanding of tissue-specific mechanisms of anti-C. auris defense and may help to pave the way for improved therapeutic options.