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

基本信息

批准号：
7448969
负责人：
Matthew J Evans
金额：
$ 9万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7448969
关键词：
Adverse effects Animal Model Antiviral Agents Antiviral Therapy Binding CD81 gene Caco-2 Cells Cell Line Cell Polarity Cells Clathrin Complex Cultured Cells Development Effectiveness Endogenous Factors Event Exhibits Fibrosis Foundations Future Genetic Genotype Glycoproteins Glycosaminoglycans Goals HCV screening Head Hepatitis C Hepatitis C virus Hepatocyte Human Individual Infection Integration Host Factors Interferons Intestines Investigation Label Laboratory Research Life Cycle Stages Liver Failure Liver diseases Location Mediating Mus Mutation Nature Phase Play Process Proteins Public Health RNA replication Recycling Research Research Personnel Retroviridae Role SR-BI receptor System Temperature Tight Junctions Transplantation United States Viral Viral Proteins Virion Virus Virus Diseases Virus Replication Work anti-hepatitis C base career cell type claudin-1 protein env Gene Products expression cloning graft failure human PHEMX protein improved inhibitor/antagonist innovation insight liver transplantation monolayer mutant novel particle pathogen polarized cell prevent programs receptor research study

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the leading cause of liver disease in the United States. With no specific anti-HCV therapies, the currently employed interferon-based treatment is inadequate, as it has severe side effects and is only effective in half of the major genotype infected individuals. My past, current, and future research is aimed at 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, little is know as to how they are utilized by the virus. Our recent identification of the 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, which I will pursue further in the independent phase of my career as the head of an academic research laboratory. Liver failure from HCV is the leading cause of liver transplantation, which is often unsuccessful due to universal reinfection after transplantation, frequently resulting in rapid fibrosis progression and subsequent graft failure. The proposed experiments, aimed at further understanding the HCV entry process, are directly related to the development of novel antiviral therapies to inhibit HCV cell entry, which could prevent graft reinfection and thus greatly improve the effectiveness of liver transplantation. In addition, this work is directly related to the development of much needed HCV small animal models.

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国肝病的主要原因。由于没有特定的抗HCV疗法，目前采用的基于干扰素的治疗不足，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。我的过去，当前和未来的研究旨在理解HCV复制机制，其最终目标是发现新型的抗病毒药靶标。过去，我研究了如何调节HCV复制，病毒蛋白如何相互相互作用以及细胞因子，并帮助建立了研究细胞培养中HCV的系统。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，这是对过程的了解不足。特别是，尽管几个宿主因素与HCV进入有关，但对病毒的使用方式知之甚少。我们最近对紧密连接蛋白Claudin-1（CLDN1）的鉴定，这对于此过程至关重要，这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。该建议将实验描述为：1）研究HCV进入极化细胞，2）定义病毒粒子如何与已知的HCV进入因子相互作用并利用3）进行额外的筛选，以使HCV进入因子能够使人类和鼠类细胞能够与HCV感染。这种调查将为HCV复制提供更大的，急需的见解，并为未来的HCV复制和其他相关病毒的复制奠定了基础，我将在我职业生涯的独立阶段作为学术研究实验室负责人进一步追求。 HCV引起的肝衰竭是肝移植的主要原因，这通常是由于移植后的普遍再感染而导致的，经常导致快速纤维化进展和随后的移植物衰竭。旨在进一步理解HCV进入过程的拟议实验与新型抗病毒疗法的发展直接相关，以抑制HCV细胞的进入，这可以防止移植物再感染，从而大大提高了肝移植的有效性。此外，这项工作与急需的HCV小动物模型的发展直接相关。