Hepatitis C virus and autophagic response

项目摘要 丙型肝炎病毒（HCV）是一种重要的人类病原体，可导致严重的肝脏疾病，包括 急、慢性肝炎、肝硬化、肝细胞癌。近年来的研究表明， HCV在体内外均能诱导自噬以增强其复制。当自噬作用 在维持细胞内稳态中的重要作用，HCV对该途径的长期干扰 在慢性感染期间可能对HCV的肝脏疾病的进展产生深远的影响- 感染的病人。尽管在过去几年中已经取得了重大进展， HCV和自噬的关系，许多问题仍然没有答案。这个目标 研究是继续我们以前的研究，以进一步了解丙型肝炎病毒和 自噬在目标1中，我们将继续我们以前的研究，以探讨生物合成途径， 自噬体在HCV感染的细胞通过识别这些膜囊泡的起源，并确定 它们是否来源于噬菌体的同型融合。正如我们最近的研究表明， HCV通过非经典途径诱导自噬，在目标2中，我们将继续描述这一途径 并研究HCV非结构蛋白在诱导该途径中的作用。此外，作为我们的 初步研究揭示了脂筏与HCV诱导的自噬体的特异性关联， 我们还将研究脂筏是如何被招募到HCV诱导的自噬体中的， 在介导自噬体膜上HCV RNA复制中的作用。我们最近开发了一种 从HCV感染细胞中纯化自噬体以鉴定其相关的 蛋白质因素在目标3中，我们将继续表征这些蛋白质因子，包括膜联蛋白A2， 载脂蛋白E和突触融合蛋白7，并确定它们在自噬体的生物发生中的可能作用 HCV复制我们提出的研究将为了解 HCV与其宿主细胞之间的相互作用，并导致更好地了解HCV的生命周期及其 发病机制它也将为理解细胞自噬途径提供重要信息， 这经常被病毒利用来增强它们的复制。

PROJECT SUMMARY Hepatitis C virus (HCV) is an important human pathogen that can cause severe liver diseases including acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Studies in recent years indicated that HCV could induce autophagy both in vitro and in vivo to enhance its replication. As autophagy plays an important role in maintaining cellular homeostasis, the prolonged perturbation of this pathway by HCV during chronic infection can have profound consequences on the progression of liver diseases in HCV- infected patients. Although significant progresses have been made during the past few years to understand the relationship between HCV and autophagy, many questions remain unanswered. The goal of this research is to continue our previous studies to further understand the relationship between HCV and autophagy. In Aim 1, we will continue our previous studies to investigate the biogenesis pathway of autophagosomes in HCV-infected cells by identifying the origin of these membrane vesicles and determine whether they are derived from the homotypic fusion of phagophores. As our recent studies indicated that HCV induced autophagy via a non-canonical pathway, in Aim 2, we will continue to delineate this pathway and examine the roles of HCV nonstructural proteins in the induction of this pathway. In addition, as our preliminary studies revealed the specific association of lipid rafts with autophagosomes induced by HCV, we will also investigate how lipid rafts are recruited to HCV-induced autophagosomes and their possible role in mediating HCV RNA replication on autophagosomal membranes. We have recently developed a novel approach to purify autophagosomes from HCV-infected cells for the identification of their associated protein factors. In Aim 3, we will continue to characterize these protein factors, which include annexin A2, apolipoprotein E and syntaxin 7, and determine their possible roles in the biogenesis of autophagosomes and HCV replication. Our proposed research will provide important information for understanding the interaction between HCV and its host cells and lead to a better understanding of the HCV life cycle and its pathogenesis. It will also provide important information for understanding the cellular autophagic pathway, which is frequently exploited by viruses to enhance their replication.