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Projekt Druckansicht

Einfluss des extrazellulären Matrixproteins Fibronektin auf die Entwicklung einer Leberfibrose

Fachliche Zuordnung Gastroenterologie
Förderung Förderung von 2012 bis 2019
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 207660558
 
Erstellungsjahr 2019

Zusammenfassung der Projektergebnisse

Liver fibrosis develops when an insult to the liver results in release of the profibrotic substance TGF-b and accumulation of extracellular matrix proteins leading to liver function impairment. The matrix consists of several proteins most notably fibronectin and collagen. These matrix proteins modify the behavior of the cell types embedded in them by acting on cell surface receptors called integrins. We therefore modified the matrix composition as well as the presence of key integrins genetically and pharmaceutically in vitro and in vivo. The lessons learned can be summarized as follows: While deletion of fibronectin in stellate cells enhances fibrosis and is thus detrimental, decreasing it pharmacologically diminishes fibrosis, possibly in part by decreasing immune cell infiltration. In line with this, decreasing collagen accumulation pharmacologically also diminishes fibrosis, but in this case it affected TGF-b amount in the matrix. In parallel, we found that deletion of b1 integrin, the main integrin subunit that binds fibronectin and collagen leads to increased TGF-b and increased fibrosis. While these data are at face value contradictory, we hypothesized that the molecule we used to prevent collagen accumulation includes a sequence able to suppress TGF-b and diminish fibrosis. Based on this we were able to identify a critical 5 amino acid sequence, which we further modified to produce a molecule that acts on a11b1 integrin diminishing TGF-b and collagen production. Testing it in vivo revealed a marked suppression of matrix accumulation and liver fibrosis. Preliminary results in a tumor model are promising. Because of the promising results in cancer, however, we will confirm the results in cancer and evaluate the efficacy in a lung fibrosis model.

Projektbezogene Publikationen (Auswahl)

 
 

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