Project Details
Projekt
TGF-β signaling and cholesterol: interdependent and druggable targets in NASH
Subject Area
Gastroenterology
Biochemistry
Biochemistry
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 437145127
Current therapies directed towards single elements of multi-layered diseases like non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are destined to limited success due to possible interdependence of the therapeutic targets. Specifically, transforming growth factor-β (TGF-β) signaling and cholesterol were implicated at several levels in liver cells at different progression stages of these liver disorders. However, the degree of their interdependence, mechanistic linkage and implications for liver disease outcome are not known. We here propose a collaborative interdisciplinary project, combining leading scientists from Germany and Israel with distinct and complementary expertise in TGF-β signaling, cholesterol/membrane biology and their role in hepatic diseases. We will employ an interdisciplinary approach to tackle the multilayered regulation of signaling by TGF-β superfamily (TβSF) ligands, specifically TGF-β1, in NAFLD/NASH with focus on the role of cholesterol. Our working hypothesis has three aspects:(i) NAFLD progression involves alterations in hepatocellular responses to TGF-β stimuli. These may comprise multiple parameters, including TGF-β receptor interactions (complex formation), receptor localization to membrane microdomains, endocytosis, proteolytic modification (shedding), exosome transfer, and downstream TGF-β signaling via Smad and non-Smad pathways.(ii) Cholesterol levels and homeostasis are altered in NAFLD/NASH progression and may modulate the response to TGF-β stimuli at the aforementioned steps from receptor binding to transcriptional control.(iii) Cholesterol/TGF-β signaling co-regulation and interaction contribute to hepatocellular fate decisions towards cellular stress, cell death and autophagy, thus inducing liver damage, or survival and epithelial-to-mesenchymal transition (EMT) to mediate carcinogenesis.
DFG Programme
Research Grants
International Connection
Israel
International Co-Applicants
Professor Marcelo Ehrlich, Ph.D.; Professor Henis Yoav, Ph.D.
