Apoptosis and Liver Fibrogenesis

描述（由申请人提供）： 肝纤维化被认为是伤口愈合过程的结果，其特征在于转化生长因子β（TGF-β）的产生和由此导致的星状细胞对胶原蛋白I合成的上调。然而，慢性肝损伤和肝纤维化之间的关系还不清楚。我们已经就慢性损伤与肝纤维化的可能机制进行了一些原创性的观察。首先，我们已经直接证明，肝星状细胞（HSC）能够在体外吞噬肝细胞的凋亡小体，第二，这导致HSC激活和上调TGF-β 1和I型胶原蛋白的产生。基于这些初步的数据，我们提出了一个中心假说，即HSC吞噬凋亡小体诱导肝纤维化。本提案的具体目标是回答由这一假设产生的两个关键问题： 1. HSC吞噬凋亡小体是一个特异的、受调控的过程吗？ HSC的吞噬作用是一种特异性受体介导的过程吗？ B）磷脂酰丝氨酸是否引发导致HSC活化的信号级联？ 2.导致TGF-β 1和1型胶原上调的信号通路是什么？ 凋亡小体的吞噬是否伴随着NADPH氧化酶的激活？ B）MAP-激酶通路的激活是否有助于I型胶原和TGF-β 1的产生？ 总之，抑制细胞凋亡、HSC对凋亡小体的吞噬或由于吞噬过程而发生的信号传导事件可能被证明是抑制肝纤维化和延迟甚至避免肝移植的治疗策略。

DESCRIPTION (provided by applicant): Hepatic fibrosis is thought to be the result of a wound-healing process, marked by transforming growth factor beta (TGF- beta) production and the resulting upregulation of collagen I synthesis by stellate cells. However the relationship between chronic liver injury and fibrogenesis is not well understood. We have made several original observations regarding a possible mechanism linking chronic injury to fibrogenesis in the liver. First, we have directly demonstrated that hepatic stellate cells (HSC) are able to phagocytose apoptotic bodies of hepatocytes in vitro, and second this results in HSC activation and upregulation of TGF-beta1 and type I collagen production. Based on these preliminary data, we propose a CENTRAL HYPOTHESIS that phagocytosis of apoptotic bodies by HSC induces fibrogenesis in the liver. The SPECIFIC AIMS of this proposal will be answering two key questions generated by this hypothesis: 1. Is phagocytosis of apoptotic bodies by HSC a specific and regulated process? A) Is phagocytosis by HSC a specific receptor-mediated process? B) Is phosphatidylserine eliciting a signaling cascade leading to HSC activation? 2. What are the signaling pathways leading to TGF-beta1 and type 1 collagen upregulation? A) Is engulfment of apoptotic bodies accompanied by activation of NADPH oxidase? B) Is the activation of the MAP-kinase pathway contributing to type I collagen and TGF-beta1 generation? In summary, inhibition of apoptosis, phagocytosis of apoptotic bodies by HSC, or signaling events occurring as a result of the phagocytic process, may prove to be therapeutic strategies to inhibit liver fibrogenesis and delay or even avoid liver transplantation.