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Identifizierung von extrazellulären Matrix-abgeleiteten Biomarkern und Zielen in dystrophischen Epidermolysis bullosa

Fachliche Zuordnung Dermatologie
Förderung Förderung von 2018 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 406802632
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

The aim of this project was to, using the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) as a paradigm of injury- and inflammation-evoked fibrosis, understand how fibrosis occurs in such a context and its wider consequences. Our strategy was to take a retrospective approach by focusing analyses on the extracellular matrix after development of fibrosis and from these conclude how the fibrosis developed. Our project revealed many important insights. We found that fibrosis in RDEB is not the consequence of changes in the abundance of major structural extracellular matrix proteins frequently associated with fibrosis, such as collagen I. In RDEB fibrosis is to a large extent the consequence of altered collagen matrix arrangement, which likely occurs through increased abundance of regulators of extracellular matrix deposition including periostin and tenascin-C. We revealed that fibrosis progression in RDEB is associated with active pro-inflammatory immunity and heightened exchange with fibroblasts. Targeting this exchange by reducing cellular activities attenuated progression of RDEB fibrosis in in vitro models and in RDEB model mice. Furthermore, using the concepts developed from understanding of fibrosis in RDEB, we could disclose mechanistically how DPP4 promotes formation of a pro-fibrotic extracellular matrix. This occurs thorough proteolysis of fibronectin molecules which alters fibronectin-guided extracellular matrix deposition. Again these findings support the idea that fibrosis is in large a consequence of altered extracellular matrix arrangement with changes in abundance of e.g. fibrillar collagens being of lesser importance for RDEB and fibroses arising in a similar context. We addressed the consequences of sensing of increasing stiffness by basal epidermal keratinocytes which occurs during fibrotic-like remodeling of the dermis. Intriguingly, our investigations revealed a link of response to increasing stiffness and altered epidermal barrier formation. Our data indicated that this is applicable to many skin inflammatory conditions and we also conceptually showed that targeting signaling pathways in keratinocytes evoked by mechanosignaling restores the appearance of the epidermal barriers. To conclude our project has provided advances in the understanding of fibrosis and its consequences, which are predicted to not be limited to RDEB but also applicable to more common skin diseases.

Projektbezogene Publikationen (Auswahl)

 
 

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