Structural dissection and dynamic insights into the molecular switch of mast cells and basophils: a blueprint for novel urticaria therapies
Grantee: Rosaria Gandini, Assistant Professor, Aarhus University
Amount: DKK 3,462,144
Grant category: Research Grants in open competition
Year: 2024
Geography: Denmark
Rosaria Gandini’s project investigates the molecular details of the IgE-FceRI complex and its functioning on mast cells and basophils in order to improve treatment opportunities for urticaria.
Urticaria, a common inflammatory skin disorder characterized by itchy wheals, angioedema, or both, manifests in acute (AU) and chronic (CU) forms. It significantly impairs patients’ quality of life, causing sleep disturbances due to pruritus, fatigue, and anxiety. The symptoms arise from the activation of skin mast cells and basophils, leading to the release of histamine and other inflammatory mediators. This activation is initiated by cross-linking and clustering of the complexes between immunoglobulin E (IgE) and its high-affinity receptor, FceRI, which is expressed on the surface of these cells.
The FceRI-IgE complex hence acts as a powerful molecular switch, which initiates the inflammatory cascade and thus provides an attractive target for drug intervention. The structural basis of this activity, however, remains open.
Rosaria Gandini’s project aims to determine the structure of the FceRI-IgE membrane complex using state of the art Cryo Electron Microscopy (cryo-EM).
Successful elucidation of the molecular details of the entire complex and its conformations will allow identification of specific regions on FceRI for targeted intervention. This knowledge will deepen the understanding of the interaction of antibodies with Fc receptors in general and may pave the way for the development of specific and effective treatment of urticaria and related disorders.
Protein stability and misfolding in keratin disorders
Grantee: Rasmus Hartmann-Petersen, Professor, University of Copenhagen
Amount: DKK 2,600,678
Grant category: Research Grants in open competition
Year: 2024
Geography: Denmark
Rasmus Hartmann-Petersen’s project aims to characterize all possible missense variants (changes in genes which introduce a different amino acid in the resulting protein) in human keratins and investigate the importance of these variants in associated diseases.
Keratins are intermediate filament proteins that form a cytoskeletal network within cells. They are expressed in a tissue-specific fashion and form heterodimers, which then further oligomerize into filaments. Variants in several keratin encoding genes are linked to a range of hereditary disorders, including several epidermal skin diseases. On the molecular level, some pathogenic keratin variants appear to cause aggregation of the keratins.
In Rasmus Hartmann-Petersen’s project it is hypothesized that most keratin-disorders are protein misfolding diseases, i.e. diseases where the underlying genetic variants cause misfolding of the encoding protein. Rasmus and his team aim to explore this hypothesis by using computational tools, including large language models (a specific form of AI). They will test the validity of the computational predictions through focused cellular studies on selected keratins and identify components regulating keratin turnover.
The results will highlight the underlying molecular mechanisms for keratin-linked human disorders and provide predictions on the severity of all possible (both known and yet unobserved) coding variants in human keratin genes. The results could be of diagnostic value, but may also highlight the cellular protein folding and protein quality control machinery as potential therapeutic targets.
Architecture of the Herpes simplex replication machinery and its inhibitors
Grantee: Eva Kummer, Associate Professor, Copenhagen University
Amount: DKK 4,902,307
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.