In vitro and in vivo analyses of the specific role of NLRP3 in the pathogenesis of fibrosis in non-alcoholic Steatohepatitis

非酒精性脂肪性肝病(NAFLD)及其进展型非酒精性脂肪性肝炎(NASH)在全球范围内呈上升趋势，这主要是由于肥胖和糖尿病这两个公认的危险因素的增加所致。在NAFLD/NASH发病数年后，一部分患者进展为肝纤维化和肝硬变，并有发展为肝细胞癌(HCC)的高风险。新的数据预测NASH将在未来几年内成为全球最常见的肝细胞癌的病因。NASH导致肝纤维化和肝硬变的病理生理途径到目前为止还不完全清楚。最常见的病理生理模型涉及肝脏炎症的中心作用，特别是NLRP3炎症体。Feldstein教授客座实验室公布的数据显示，NLRP3炎性小体激活在NASH背景下发展为肝纤维化中具有重要意义。NLRP3的持续激活导致肝脏持续炎症和肝星状细胞(HSC)的激活以及肝纤维化的发生，推测NASH肝纤维化过程中HSC通过NLRP3的分子激活是主要的信号转导途径。本研究的主要目的是通过基因敲除和基因敲除小鼠模型以及体外实验，研究NLRP3依赖的HSC在肝纤维化形成过程中的激活机制和信号转导机制。本研究获得的数据将有助于更好地理解NASH的纤维化形成机制，并可能为NASH患者的药物治疗提供新的治疗策略。

Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) show an increasing prevalence worldwide, mainly because of an increased prevalence of the well-established risk factors obesity and diabetes mellitus. Years after the onset of NAFLD/NASH a subset of patients progresses to liver fibrosis and liver cirrhosis and is at high risk of developing hepatocellular carcinoma (HCC). New data predict NASH to be the most common cause for the development of HCC worldwide within the next years.The pathophysiological pathways of progression of NASH leading to liver fibrosis and liver cirrhosis are not fully clarified up to now. The most common pathophysiological model implicates a central role of hepatic inflammation, especially the NLRP3 inflammasome. Published data of the guest laboratory of Prof. Feldstein showed a major importance of NLRP3 inflammasome activation in developing liver fibrosis in the context of NASH. Persistent activation of NLRP3 leads to continuous hepatic inflammation and activation of hepatic stellate cells (HSC) as well as liver fibrosis.This proposal hypothesizes the molecular activation of HSC via NLRP3 as the main signalling pathway during fibrogenesis in NASH. Using knock-in and knockout mice models as well as in vitro experiments the main aim of this research project is to identify the mechanisms and signalling of NLRP3-dependent activation of HSC during fibrogenesis.The data obtained by this research project will contribute to a better understanding of fibrogenesis in NASH and may reveal a new therapeutic strategy for the medical treatment of NASH patients.