Role of HCV exosomes in intercellular communication

项目主任/首席调查员(Hahn，Young S.)： 项目总结： 据估计，慢性丙型肝炎病毒感染影响着世界3%的人口(1.8亿人)，是一种 导致终末期肝病的世界性健康问题，包括肝细胞癌(HCC)。这个 丙型肝炎病毒相关性肝细胞癌的发生是由晚期纤维化或肝硬变引起的。丙型肝炎的临床转归 感染和肝癌的风险取决于促炎和抗炎细胞因子之间的平衡以及 肝脏发炎。我们的初步数据显示，从感染丙型肝炎病毒的肝细胞释放的外切体含有 转化生长因子-β等免疫调节分子。重要的是，丙型肝炎病毒外切酶来源于感染的肝细胞。 促进与非实质细胞如M、φ和LSec的细胞间通讯。由于…… 在接受丙型肝炎病毒外体的信号后，Mφ和LSec被分化为纤维化细胞，激活星状细胞 细胞，并诱导肝纤维化的发展。该项目的总体目标是通过以下方式定义该机制 感染肝细胞中哪些丙型肝炎病毒外切体驱动肝纤维化微环境及探讨 预防肝纤维化的潜在治疗药物。在目标1中，我们建议识别关键的分子机制 在体外和体内，丙型肝炎病毒感染后肝细胞外切体的分泌所需。在目标2中，我们将 确定丙型肝炎病毒来源的外切体如何诱导纤维化的M2样Mφ的激活。在目标3中，我们将确定 丙型肝炎病毒来源的外切体如何诱导纤维性LSEC分化及探索治疗策略 预防纤维化。这里提出的研究将为确定驾驶的关键因素开辟新的天地 有利于肝纤维化的微环境，将有助于开发预防肝脏的新的治疗靶点 纤维化症。 PHS 398/2590(06/09版)页面续格式页面

Program Director/Principal Investigator (Hahn, Young S.): Project Summary: Chronic HCV infection affects an estimated 3% of the world's population (>180 million people) and is a worldwide health problem causing end-stage liver diseases including hepatocellular carcinoma (HCC). The development of HCV-related HCC occurs by advanced fibrosis or cirrhosis. The clinical outcome of HCV infection and HCC risk depends on a balance between pro- and anti-inflammatory cytokines and the severity of liver inflammation. Our preliminary data show that exosomes released from HCV-infected hepatocytes contain the immunoregulatory molecules such as TGF-β. Importantly, HCV exosmes derived from infected hepatocytes promote intercellular communication with non-parenchymal cells such as Mφ and LSEC. As a result of receiving signaling from HCV exosomes, Mφ and LSEC are differentiated into fibrotic cells, that activate stellate cells and induce the development of liver fibrosis. The overall goal of this project is to define the mechanism by which HCV-derived exosomes from infected hepatocytes drive pro-fibrotic liver microenvironment and explore potential therapeutic agents to prevent liver fibrosis. In Aim 1, we propose to identify key molecular machinery required for the secretion of hepatocyte exosomes after HCV infection in in vitro and in vivo. In Aim 2, we will determine how HCV-derived exosomes induce the activation of fibrotic M2-like Mφ. In Aim 3, we will determine how HCV-derived exosomes induce fibrotic LSEC differentiation and explore a therapeutic strategy for preventing fibrosis. The studies proposed here will break new ground for identifying factors crucial for driving pro-fibrotic liver microenvironment and will help to develop novel therapeutic targets for the prevention of liver fibrosis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page