Goals 1. to investigate the signal transduction pathways leading to excessive apoptosis in inflammatory disorders of the liver and gastrointestinal tract 2. to develop anti-apoptotic therapies for these inflammatory disorders Background In many diseases of liver and gastrointestinal tract, functional epithelial cells are exposed to cytokines, oxidative stress and bile acids, resulting in necrotic and apoptotic cell death and loss of organ function. Apoptotic cell death is a highly regulated process and has been observed in liver diseases and inflammatory bowel diseases. Apoptotic cell death occurs when pro-apoptotic forces overrule anti-apoptotic forces. Elucidation of the signal transduction pathways leading to the activation of pro- and anti-apoptotic proteins is therefore essential in the identification of novel targets for anti-apoptotic therapy. In our research we specifically aim to block apoptotic signals originating from mitochondria, using anti-apoptotic proteins regulated by the transcription factors NF-kB and AP-1.
Hepatocytes, the parenchymal liver cells, are exposed to pro-apoptotic agents like cytokines (TNF, FasLigand), oxidative stress and bile acids in many liver diseases. Cytokines (TNF, FasL) activate receptor-mediated apoptosis, involving caspase-8 activation and cleavage of the Bcl-2 family member Bid into the pro-apoptotic fragment tBid. Exposure to oxidative stress and bile acids results in the release of pro-apoptotic proteins from mitochondria into the cytoplasm. These proteins include cytochrome c, which activates caspase-9 and Smac/Diablo and HtrA2 which block caspase inhibitors of the IAP family (Inhibitors of APoptosis). Mitochondrial membrane integrity is further regulated by Bcl-2 family members such as anti-apoptotic Bcl-2, A1/Bfl-1 and Bcl-xl and pro-apoptotic Bak, Bax, Bad. Survival pathways are activated by TNF (NF-kB pathway) and oxidative stress and bile acids (AP-1 pathway) leading to increased transcription of anti-apoptotic NF-kB regulated genes like A1/Bfl-1; IAP-2 and AP-1 regulated genes like HO-1 (Heme-oxygenase-1) and Mn-superoxide dismutase (MnSOD). The balance between pro- and anti-apoptotic factors determines whether the cell will survive or not. |
