Project Details
Projekt
Role of the Bcl-2 family and TRAIL signaling in paracetamol-induced necrosis in liver cells
Applicant
Professor Dr. Thomas Brunner
Subject Area
Pharmacology
Pathology
Cell Biology
Pathology
Cell Biology
Term
from 2014 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 232935877
The liver has important functions in the storage and metabolism of nutrients. Due to its extensive vascularization it is, however, also frequent target of various pathogen-associated immunopathologies and adverse drug side-effects. Paracetamol (APAP) is a widely used drug with analgesic and anti-pyretic properties. Although considered safe at therapeutic doses, accidental or intentional APAP overdose may cause severe liver damage and even death. The underlying mechanisms of APAP-induced hepatocyte death and associated liver failure are incompletely understood, although necrosis rather than apoptosis appears to be responsible for mediating liver damage. We have previously shown that Bcl-2 family members critically contribute to APAP-induced liver damage, in a process, which amplified by TRAIL receptor signaling. More recently we have seen that the pro-apoptotic BH3-only proteins Bim, Noxa and Puma are induced in hepatocytes upon APAP treatment. The specific aims of this project are therefore to understand the mechanisms by which APAP promotes the expression of these Bcl-2 homologs, what their respective role is in APAP-induced liver damage, how Bcl-2 family members interact with or regulate this necrotic form of cell death, and finally how TRAIL signaling regulates APAP-induced hepatocyte death. The results obtained in this study will shed new light into the role of Bcl-2 homologs in this form of drug-induced liver damage in general and in necrotic cell death in particular, and how TRAIL signaling interacts with these processes. Last but not least this study may help to identify novel potential targets to develop new drugs for the treatment of APAP intoxication and associated liver damage.
DFG Programme
Research Units
