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Virus-host interactions in replication complex assembly

复制复合体组装中病毒与宿主的相互作用

基本信息

批准号：
7577544
负责人：
DAVID J MILLER
金额：
$ 28.28万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2010-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7577544
关键词：
Abbreviations Affinity Chromatography Alphanodavirus Antiviral Agents Binding Biochemical Cells Clinical Complex DNA-Directed RNA Polymerase Drosophila genus Drosophila melanogaster Event Family Family Picornaviridae Flaviviridae Functional RNA Genome Genomics Glutathione S-Transferase Goals Heat shock proteins Hemagglutinin Hepatitis C virus Hour Housing In Vitro Infection Insecta Integration Host Factors Intracellular Membranes Isoelectric Focusing Link MALDI-TOF Mass Spectrometry Macromolecular Complexes Mass Spectrum Analysis Membrane Membrane Proteins Mitochondria Modeling Molecular Molecular Chaperones Molecular Genetics Mutation Outcome Outer Mitochondrial Membrane Physical Examination Polyacrylamide Gel Electrophoresis Process Protein Analysis Proteins RNA RNA Interference RNA Viruses RNA replication RNA-Directed RNA Polymerase Research Research Personnel Role SARS coronavirus Saccharomyces cerevisiae Signal Transduction Sodium Dodecyl Sulfate-PAGE Staging Structure Syndrome Testing Togaviridae Validation Viral Viral Pathogenesis Viral Proteins Virus Virus Diseases Virus Replication West Nile virus Yeasts cell type design effective therapy human disease insight member mitochondrial membrane novel pathogen premature prevent programs protein complex receptor research study translocase viral RNA virus host interaction

项目摘要

Viral pathogenesis is intimately linked with dynamic and complex host-pathogen interactions. The mechanisms underlying these essential interactions, in particular those shared by viruses with similar genomic structures, represent attractive potential targets for antiviral drugs. Viruses that contain a positive-sense single-stranded RNA genome, such as hepatitis C virus, West Nile virus, and the SARS coronavirus, represent a diverse group of pathogens responsible for significant human diseases for which few effective therapies exist. Despite the varied clinical syndromes caused by these viruses, all characterized positive-strand RNA viruses use intracellular membranes for viral RNA replication complex formation and function. However, the mechanisms whereby viral RNA replication complexes assemble on specific intracellular membranes are not well understood. The long-term objectives of this project are to elucidate the host-pathogen interactions that facilitate positive-strand RNA virus replication complex assembly and function. A detailed understanding of these interactions will provide insight into the mechanisms of viral pathogenesis, and potentially identify novel targets for broadly effective antiviral drugs. The specific focus of this proposal is to define the early events in viral RNA replication complex assembly. The targeting, transport, and initial interactions of virus-encoded RNA replication complex proteins with intracellular membranes are essential steps in replication complex assembly, and therefore are important determinants of viral pathogenesis. The general strategy of the proposed research is to use Flock house virus, an established and versatile model used to study positive-strand RNA virus structure and replication, to investigate the mechanisms of viral RNA replication complex assembly. Biochemical, molecular, and genetic approaches will be used to investigate the targeting and transport of the Flock house virus RNA-dependent RNA polymerase to intracellular membranes. The specific aims of this proposal are designed to accomplish two goals: 1) understand the role of cellular chaperone proteins in Flock house virus RNA replication complex assembly; and 2) define the membrane receptor responsible for Flock house virus RNA replication complex intracellular localization.

病毒的发病机制与动态和复杂的宿主-病原体相互作用密切相关。的这些基本相互作用的潜在机制，特别是具有相似基因组结构的病毒所共有的机制，代表了抗病毒药物的有吸引力的潜在靶点。含有正义单链RNA基因组的病毒，如丙型肝炎病毒、西尼罗河病毒和SARS冠状病毒，代表了一组不同的病原体，这些病原体负责重大的人类疾病，而这些疾病几乎没有有效的治疗方法。尽管由这些病毒引起的临床综合征多种多样，但所有特征性的正链RNA病毒都使用细胞内膜进行病毒RNA复制复合物的形成和功能。然而，病毒RNA复制复合物在特定细胞内组装的机制，膜还没有被很好地理解。本项目的长期目标是阐明促进正链RNA病毒复制复合物组装和功能的宿主-病原体相互作用。对这些相互作用的详细了解将有助于深入了解病毒的发病机制，并可能为广泛有效的抗病毒药物确定新的靶点。该提案的具体重点是定义病毒RNA复制复合物组装中的早期事件。病毒编码的RNA复制复合物蛋白与细胞内膜的靶向、转运和初始相互作用是复制复合物组装的重要步骤，因此是病毒发病机制的重要决定因素。的本研究的总体策略是利用Flock house病毒（一种用于研究正链RNA病毒结构和复制的已建立的通用模型）来研究病毒RNA复制复合物组装的机制。生物化学，分子和遗传学方法将被用来研究靶向和运输的弗洛克豪斯病毒RNA依赖的RNA聚合酶的细胞内膜。该提案的具体目的旨在实现两个目标：1）了解细胞伴侣蛋白在Flock house病毒RNA复制复合物组装中的作用; 2）确定负责Flock house病毒RNA复制复合物细胞内定位的膜受体。