Role of HCV exosomes in intercellular communication

项目负责人/主要研究者（Hahn，Young S.）： 项目摘要： 慢性HCV感染影响估计3%的世界人口（> 1.8亿人），并且是一种慢性病毒感染。 肝细胞癌（HCC）是导致包括肝细胞癌（HCC）在内的终末期肝病的全球性健康问题。的 HCV相关的HCC的发展发生于晚期纤维化或肝硬化。丙型肝炎的临床转归 感染和HCC风险取决于促炎细胞因子和抗炎细胞因子之间的平衡以及 肝脏炎症我们的初步数据显示，从HCV感染的肝细胞释放的外来体含有 免疫调节分子如TGF-β。重要的是，来自感染肝细胞的HCV外泌体 促进与非实质细胞如Mφ和LSEC的细胞间通讯。的结果 接受来自HCV外泌体的信号，Mφ和LSEC分化为纤维化细胞，其激活星形胶质细胞， 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： 来自受感染肝细胞的HCV衍生外泌体驱动促纤维化肝脏微环境并探索 预防肝纤维化的潜在治疗剂。在目标1中，我们提出确定关键的分子机制， 体外和体内HCV感染后肝细胞外泌体分泌所需的蛋白质。在目标2中，我们将 确定HCV衍生的外泌体如何诱导纤维化M2样Mφ的活化。在目标3中，我们将确定 HCV衍生外来体如何诱导纤维化LSEC分化并探索治疗策略 防止纤维化。这里提出的研究将为确定驾驶的关键因素开辟新的天地 促纤维化肝脏微环境，并将有助于开发新的治疗靶点，用于预防肝脏纤维化。 纤维化 PHS 398/2590（Rev.06/09）

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