Epigenetic regulation of sebaceous gland development and homeostasis
Grantee: Brian Capell, Assistant Professor, University of Pennsylvania
Amount: DKK 2,885,457
Grant category: Research Grants in open competition
Year: 2024
Geography: USA
Brian Capell’s project seeks to better understand how epigenetic changes (modifications that do not change the sequence of genomic DNA) regulate the development of sebaceous glands.
Dysfunction of sebaceous glands (SGs) has been linked to a variety of common skin disorders ranging from atopic dermatitis to acne, sebaceous hyperplasia, seborrheic dermatitis and sebaceous tumors.
Brian Capell and his team have recently discovered that through genetic modification of the epigenome, they could promote a dramatic increase in the number and size of SGs (Ko, et al. Developmental Cell. In press. 2024). This surprising result demonstrated the direct role that epigenetics and chromatin organization plays in controlling SG development and abundance. It also suggested that targeting the epigenome might offer new ways to treat disorders characterized by aberrant SG development and activity.
Diseases related to aberrant SG development or activity can have a deleterious effect on both human physical and mental health. Despite this, very little is known of the role of epigenetics in SG development and homeostasis. To address this, Brian Capell’s project aims to test the influence of epigenomic modifiers and modifications upon SG development and disease to further dissect their contribution to the pathogenesis of these very common conditions.
Collectively, this project will address outstanding questions regarding the role of the epigenome in SG development and homeostasis and in common diseases driven by SG dysfunction – diseases that are both understudied and in need of better therapies.
Endothelial senescence in the pathogenesis of systemic sclerosis
Grantee: Eliza Pei-Suen Tsou, Assistant Professor, University of Michigan
Amount: DKK 3,990,092
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.
Understanding structural and functional differences between JAK family JH1 and JH2 domains
Grantee: Christopher Bunick, Associate Professor, Yale University
Amount: DKK 4,165,955
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.
Skin microbiome-metabolome modulation of skin homeostasis
Grantee: Julia Oh, Associate Professor, The Jackson Laboratory
Amount: DKK 3,953,521
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.