Role of the Bcl-2 family and TRAIL signaling in paracetamol-induced necrosis in liver cells

Bcl-2 家族和 TRAIL 信号在扑热息痛诱导的肝细胞坏死中的作用

• 批准号: 245712680
• 负责人: Professor Dr. Thomas Brunner
• 金额: --
• 依托单位: Lehrstuhl für Biochemische Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245712680?language=en
• 关键词: Role; Bcl; family; TRAIL; signaling

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.

肝脏在营养物质的储存和代谢中起着重要的作用。然而，由于其广泛的血管形成，它也经常成为各种病原体相关免疫病理和药物副作用的靶点。扑热息痛(APAP)是一种广泛使用的具有镇痛和解热作用的药物。尽管在治疗剂量下被认为是安全的，但意外或故意过量服用APAP可能会导致严重的肝脏损害，甚至死亡。APAP诱导的肝细胞死亡和相关的肝衰竭的潜在机制尚不完全清楚，尽管似乎是坏死而不是细胞凋亡是介导肝损伤的原因。我们先前已经证明，Bcl2家族成员在APAP诱导的肝损伤中起关键作用，该过程被TRAIL受体信号放大。最近，我们看到APAP治疗后，肝细胞中只有BH3促凋亡蛋白Bim、Noxa和Puma被诱导。因此，本项目的具体目的是了解APAP促进这些Bcl2同源物表达的机制，它们在APAP诱导的肝损伤中各自发挥的作用，Bcl2家族成员如何与这种坏死形式的细胞死亡相互作用或调节，以及TRAIL信号如何调节APAP诱导的肝细胞死亡。这项研究的结果将为了解Bcl2同系物在这种形式的药物诱导的肝损伤中的作用，特别是在坏死性细胞死亡中的作用，以及TRAIL信号如何与这些过程相互作用提供新的线索。最后但并非最不重要的是，这项研究可能有助于确定新的潜在靶点，以开发治疗APAP中毒和相关肝损伤的新药。