Characterization of functional TGF-beta signaling networks that promote hepatic fibrogenesis through epithelial-mesenchymal transition in hepatocytes

通过肝细胞上皮间质转化促进肝纤维化的功能性 TGF-β 信号网络的表征

• 批准号: 136948895
• 负责人: Professor Dr. Steven Dooley, Ph.D.
• 金额: --
• 依托单位: II. Medizinische Klinik: Gastroenterologie, Hepatologie, Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/136948895?language=en
• 关键词: Characterization; functional; TGF; beta; signaling

This proposal aims at elucidating hepatocytic epithelial mesenchymal transition (EMT) in vitro and its role in chronic liver diseases (CLD). TGF-b-dependent EMT in hepatocytes will be investigated with emphasis on cross-communicating signaling pathways acting complementary on the fibrogenic outcome. In murine CLD models based on different inciting injuries, temporal and spatial analyses will be conducted to determine the onset of hepatocyte EMT. Complementary studies will be performed with human tissues at different stages of CLD (ASH, NASH, HBV, HCV, Schistosomiasis) by immunohistochemical investigation of EMT. Given (i) the pivotal role of Snail in EMT and (ii) its significant transcriptional activation by TGF-b in hepatocytes and fibrotic liver diseases, Snail overexpressing and Snail knock out mice will be set up to study the functional impact on hepatocyte EMT and fibrogenic responses in CLD. The expected results will provide novel insights into the mechanisms underlying fibrogenesis and may pave the way for specific interventions, such as hepatocyte-specific drugs for hepatic diseases.

本研究旨在阐明体外肝细胞上皮间质转化（EMT）及其在慢性肝病（CLD）中的作用。肝细胞中的TGF-β依赖性EMT将被研究，重点是对纤维化结果起补充作用的交叉通信信号通路。在基于不同诱发损伤的鼠CLD模型中，将进行时间和空间分析以确定肝细胞EMT的发生。将通过EMT的免疫组织化学研究，对CLD不同阶段（ASH、NASH、HBV、HCV、血吸虫病）的人体组织进行补充研究。鉴于（i）Snail在EMT中的关键作用和（ii）其在肝细胞和纤维化肝病中通过TGF-β的显著转录激活，将建立Snail过表达和Snail敲除小鼠以研究对CLD中肝细胞EMT和纤维化反应的功能影响。预期的结果将为纤维形成的机制提供新的见解，并可能为特定的干预措施铺平道路，例如肝细胞特异性药物治疗肝脏疾病。