Studies of hepatitis C virus polarized cell entry and host factor requirements

丙型肝炎病毒极化细胞进入和宿主因子要求的研究

• 批准号: 7707255
• 负责人: Matthew J Evans
• 金额: $ 24.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707255
• 关键词: Adverse effects; Animal Model; Antiviral Agents; Antiviral Therapy; Area; Baculoviruses; Cell Culture Techniques; Cell Polarity; Cells; Development; Effectiveness; Event; Family; Fibrosis; Flaviviridae; Foundations; Future; Genotype; Goals; HCV screening; Head; Hepatitis C virus; Hepatocyte; Human; Individual; Integration Host Factors; Interferons; Investigation; Laboratories; Laboratory Research; Life Cycle Stages; Liver Failure; Liver diseases; Mus; Nature; Phase; Population; Process; Research; Retroviridae; Rice; System; Techniques; Tight Junctions; Time Study; Transplantation; United States; Viral; Viral Proteins; Virion; Virus; Virus Replication; Work; anti-hepatitis C; base; career; claudin-1 protein; combat; design; effective therapy; fascinate; graft failure; improved; insight; liver transplantation; novel; polarized cell; prevent; research study; virology

Hepatitis C virus (HCV) is the leading cause of liver disease in the United States. With no specific anti-HCV therapies, the cun-ently employed interferon-based treatment is inadequate, as it has severe side effects and is only effective in half of the major genotype infected individuals. The research proposed in this application is aimed at furthering the understanding the HCV replication mechanisms, with the ultimate goal of . . uncovering novel antiviral targets. In the past, I have studied how HCV replication is regulated, how viral proteins interact with each other and cellular factors, and helped establish systems to study HCV in cell culture. Currently, my research is focused on the earliest events in the viral life cycle involving entry into the host cell, which are poorly understood processes. In particular, although several host factors have been implicated as involved in HCV entry, litt|e is know as to how they are utilized by the virus. Our recent identification ofthe tight junction protein, claudin-1 (CLDN1), as essential for this process was a major development in this field. This discovery has opened-up a whole new view of HCV cell entry, as the involvement of CLDN1 in cell polarity strongly suggests that the polarized nature of an hepatocyte may influence how HCV enter a cell. This proposal describes experiments to; 1) study HCV entry into polarized cells, 2) define how the virion interacts with and utilizes the known HCV entry factors, and 3) perform additional screens for HCV entry factors able to render both human and murine cells infectable with HCV. Such investigations will provide greater, much needed insight in HCV replication, as well as lay the foundation for future studies of replication of HCV and other related viruses.

丙型肝炎病毒（HCV）是美国肝病的主要原因。没有特定的抗HCV 疗法，基于干扰素的Cun使用的治疗不足，因为它具有严重的副作用，并且 仅在一半的主要基因型感染个体中有效。该应用程序提出的研究 旨在以最终的目标进一步了解HCV复制机制。 。 揭示新的抗病毒靶标。过去，我研究了HCV复制的调节方式，病毒程度如何 蛋白质相互相互作用和细胞因子，并帮助建立了研究细胞中HCV的系统 文化。目前，我的研究集中于病毒生命周期中最早的事件，涉及进入 宿主细胞，这些细胞知之甚少。特别是，尽管有几个宿主因素是 Litt | e涉及与HCV进入的有关，该病毒是如何使用的。我们最近 识别紧密连接蛋白Claudin-1（CLDN1）对于此过程至关重要的是该领域的主要发展。由于CLDN1在细胞极性中的参与强烈表明，肝细胞的极化性质可能影响HCV进入细胞的方式，因此这一发现打开了HCV细胞进入的全新视图。该建议描述了实验； 1）研究HCV进入偏振细胞，2）定义病毒粒子如何与已知的HCV进入因子相互作用并使用3）对HCV进入因子进行额外的筛选，以使能够使HCV感染的人类和鼠类细胞同时使人类和鼠类细胞同时使人类和鼠类细胞具有感染。 此类调查将为HCV复制提供更大的，急需的见解，并介绍 基础HCV和其他相关病毒的复制研究基础。