Nonstructural 4B Protein and Hepatitus C Virus Production
非结构 4B 蛋白和丙型肝炎病毒生产
基本信息
- 批准号:8527703
- 负责人:
- 金额:$ 18.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-15 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:Antiviral AgentsApoptosisBindingBiological AssayBiological MarkersC-terminalCSNK2A1 geneCancer EtiologyCell SurvivalCell physiologyChimera organismCo-ImmunoprecipitationsComplexCoupledDNA Sequence RearrangementDefectDevelopmentDiseaseDrug TargetingEventGenomeGenotypeGoalsGuanosine Triphosphate PhosphohydrolasesHepatitis C virusInfectionInfectious hepatitidesIntegration Host FactorsLeadMAP2K1 geneMalignant NeoplasmsMalignant neoplasm of liverMapsMass Spectrum AnalysisMembraneMusMutationPathogenesisPathway interactionsPatientsPhosphorylationPhosphotransferasesPlayProcessProductionProtein CProteinsRNA BindingRNA VirusesRegulationRelative (related person)ReportingResearchRoleSpecificitySurface Plasmon ResonanceTestingUnited StatesViralViral ProteinsVirionVirusVirus AssemblyVirus DiseasesVirus Replicationbasecrosslinkdrug developmentin vivoinsightliver transplantationnovelparticletumorviral RNAvirus host interaction
项目摘要
DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a positive strand RNA virus that establishes both persistent infection in patients and causes cancer. The long-term goal of my research is to elucidate the mechanisms whereby the nonstructural 4B (NS4B) protein facilitates virus production and pathogenesis. There is growing evidence that NS4B facilitates virion production. However, NS4B switch from the replication to the particle formation mode is currently unknown. Further, we know little about the virus and host interactions leading up to NS4B regulation of virion production. Hence, the objective of this application is to gain a better insight into the contribution of NS4B to virus production and the underlying mechanism. We postulate that: [1] During infection, NS4B binds to several virus proteins and regulates their activities, which in the case of NS5A is via p58 formation by host kinases; [2] Specific residues in the NS4B protein contribute to NS5A p58 formation and virion production; [3] JFH1 chimera that are defective in NS5A p58 formation have fewer host kinases interacting with NS5A relative to Wt JFH1. Through a better understanding of NS4B role in virion production, novel antiviral targets for drug development could be uncovered. Thus, we propose the following Specific Aims. Aim 1. Map the NS4B residues required for virus production and NS5A p58 formation; investigate the subcellular distribution of NS5A in the JFH1 chimera; examine the possibility that the adapted viruses have regained the Wt NS5A p58 levels and the underlying mechanism. In this aim, we postulate that specific residues in NS4B are facilitating virus production whereas others are important for HCV replication. Mapping such regions/residues is key to understanding how NS4B can play two important but distinct roles in HCV lifecycle. Hence, we will: [1] Map the NS4B residues required for virus production and NS5A p58 formation, [2] Investigate the subcellular distribution of NS5A p58 during chimeric virus infection and, [3] examine the possibility that the adapted viruses have regained the Wt NS5A p58 levels and the underlying mechanism. Aim 2. Identify virus factors associated NS4B or host factors associated with NS5A p58 and NS4B; examine their roles in virion production. Here, we postulate that NS4B binds to virus factors, leading to a switch from replication to virion production. For instance, NS4B may cause a conformational change in NS5A that favors p58 formation by host kinases. Conversely, NS4B binds to host kinases and causes them to hyperphosphorylate NS5A. Thus, we will: identify [1] NS4B virus/host partners, [2] NS5A p58 host partners and, [3] use surface plasmon resonance to confirm binding and specificity as well as the significance on HCV replication and virion production. We will search for kinases and other host factors associated with NS4B or NSS5A p58. Indeed, kinases regulate various cellular processes and are often targets for treatment of numerous diseases including cancers. Hence, insight into the role of these factors in virion production can lead to the development of novel drugs targeting HCV and the resulting HCC.
描述(由申请方提供):丙型肝炎病毒(HCV)是一种正链RNA病毒,可在患者中建立持续感染并导致癌症。我的研究的长期目标是阐明非结构4 B(NS 4 B)蛋白促进病毒产生和致病的机制。越来越多的证据表明NS 4 B促进了病毒体的产生。然而,NS 4 B从复制到颗粒形成模式的切换目前尚不清楚。此外,我们对导致NS 4 B调节病毒体产生的病毒和宿主相互作用知之甚少。因此,本申请的目的是更好地了解NS 4 B对病毒生产的贡献及其潜在机制。我们假设:[1]在感染过程中,NS 4 B与几种病毒蛋白结合并调节它们的活性,在NS 5A的情况下,这是通过宿主激酶形成p58; [2] NS 4 B蛋白中的特定残基有助于NS 5A p58形成和病毒体产生; [3]相对于Wt JFH 1,NS 5A p58形成缺陷的JFH 1嵌合体具有较少的宿主激酶与NS 5A相互作用。通过更好地了解NS 4 B在病毒体产生中的作用,可以发现用于药物开发的新的抗病毒靶点。因此,我们提出以下具体目标。目标1。绘制病毒生产和NS 5A p58形成所需的NS 4 B残基;研究NS 5A在JFH 1嵌合体中的亚细胞分布;检查适应病毒恢复Wt NS 5A p58水平的可能性和潜在机制。在这个目标中,我们假设NS 4 B中的特定残基促进病毒的产生,而其他残基对HCV复制很重要。定位这些区域/残基是理解NS 4 B如何在HCV生命周期中发挥两个重要但不同作用的关键。因此,我们将:[1]绘制病毒产生和NS 5A p58形成所需的NS 4 B残基,[2]研究嵌合病毒感染期间NS 5A p58的亚细胞分布,[3]检查适应病毒恢复Wt NS 5A p58水平的可能性和潜在机制。目标二。鉴定与NS 4 B相关的病毒因子或与NS 5A p58和NS 4 B相关的宿主因子;检查它们在病毒体产生中的作用。在这里,我们假设NS 4 B与病毒因子结合,导致从复制到病毒体生产的转变。例如,NS 4 B可能导致NS 5A的构象变化,有利于宿主激酶形成p58。相反,NS 4 B与宿主激酶结合并导致它们过度磷酸化NS 5A。因此,我们将:鉴定[1] NS 4 B病毒/宿主配偶体,[2] NS 5A p58宿主配偶体,[3]使用表面等离子体共振确认结合和特异性以及对HCV复制和病毒体产生的意义。我们将寻找与NS 4 B或NSS 5A p58相关的激酶和其他宿主因子。事实上,激酶调节各种细胞过程,并且通常是治疗包括癌症在内的许多疾病的靶标。因此,深入了解这些因素在病毒体产生中的作用可以开发出针对丙型肝炎病毒和由此产生的肝癌的新型药物。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kouacou V. KONAN其他文献
Kouacou V. KONAN的其他文献
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{{ truncateString('Kouacou V. KONAN', 18)}}的其他基金
Nonstructural 4B Protein and Hepatitus C Virus Production
非结构 4B 蛋白和丙型肝炎病毒生产
- 批准号:
8227488 - 财政年份:2012
- 资助金额:
$ 18.57万 - 项目类别:
Nonstructural 4B protein and hepatitis C virus replication complex
非结构 4B 蛋白和丙型肝炎病毒复制复合物
- 批准号:
8280840 - 财政年份:2011
- 资助金额:
$ 18.57万 - 项目类别:
Hepatitis C Virus Replication and Intracellular Membrane Rearrangement
丙型肝炎病毒复制和细胞内膜重排
- 批准号:
7681093 - 财政年份:2007
- 资助金额:
$ 18.57万 - 项目类别:
Hepatitis C Virus Replication and Intracellular Membrane Rearrangement
丙型肝炎病毒复制和细胞内膜重排
- 批准号:
7302898 - 财政年份:2007
- 资助金额:
$ 18.57万 - 项目类别:
Hepatitis C Virus Replication and Intracellular Membrane Rearrangement
丙型肝炎病毒复制和细胞内膜重排
- 批准号:
7499107 - 财政年份:2007
- 资助金额:
$ 18.57万 - 项目类别:
Hepatitis C Virus Replication and Intracellular Membrane Rearrangement
丙型肝炎病毒复制和细胞内膜重排
- 批准号:
7938201 - 财政年份:2007
- 资助金额:
$ 18.57万 - 项目类别:
HCV Nonstructural Proteins and Host Protein Secretion
HCV 非结构蛋白和宿主蛋白分泌
- 批准号:
6460335 - 财政年份:2002
- 资助金额:
$ 18.57万 - 项目类别:
HCV Nonstructural Proteins and Host Protein Secretion
HCV 非结构蛋白和宿主蛋白分泌
- 批准号:
7071269 - 财政年份:2002
- 资助金额:
$ 18.57万 - 项目类别:
HCV Nonstructural Proteins and Host Protein Secretion
HCV 非结构蛋白和宿主蛋白分泌
- 批准号:
6623018 - 财政年份:2002
- 资助金额:
$ 18.57万 - 项目类别:
HCV Nonstructural Proteins and Host Protein Secretion
HCV 非结构蛋白和宿主蛋白分泌
- 批准号:
6763072 - 财政年份:2002
- 资助金额:
$ 18.57万 - 项目类别:
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