Characterization of a host hepatocyte factor that regulates HCV replication

调节 HCV 复制的宿主肝细胞因子的表征

• 批准号: 8082731
• 负责人: Andrew W. Tai
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082731
• 关键词: 1-Phosphatidylinositol 4-Kinase; Adverse effects; Affect; Affinity; Affinity Chromatography; Award; Binding; Biochemical; Biological Models; Cell physiology; Cells; Cellular Membrane; Cellular Morphology; Chronic; Chronic Hepatitis C; Complex; Data; Dependence; Event; Feedback; Fluorescence Microscopy; Genome; Genotype; Goals; Health Benefit; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Image; Individual; Infection; Internal Ribosome Entry Site; Internet; Lead; Libraries; Life; Life Cycle Stages; Liver diseases; Membrane; Membrane Proteins; Mentors; Modeling; Molecular; Molecular Virology; Morphogenesis; Organelles; Pathway interactions; Phosphatidylinositols; Polyproteins; Population; Process; Proteins; Public Health; RNA Interference; RNA Viruses; RNA chemical synthesis; Replicon; Research; Review Committee; Role; Screening procedure; Small Interfering RNA; Specificity; System; Systems Development; Techniques; Testing; Therapeutic Agents; Training Programs; Translations; United States National Institutes of Health; Viral; Virus; Virus Replication; base; cellular imaging; cofactor; functional genomics; liver transplantation; novel; novel therapeutics; optical imaging; phosphatidylinositol 4-phosphate; replicase; research study; skills; trafficking; viral RNA

DESCRIPTION (provided by applicant): Chronic hepatitis C virus (HCV) infection develops in 70-80% of all exposed individuals and affects 3% of the world's population. There is a need for more effective and better-tolerated HCV therapies. Our long-term goals are to define host-HCV molecular interactions and in so doing, to identify novel therapeutic agents for HCV therapy. We have completed a functional genomic screen for host cofactors for HCV replication using a whole- genome siRNA library. Among the many novel host cofactors identified is PI4KA, a phosphatidylinositol 4- kinase (PI 4-kinase). We hypothesize that PI4KA is necessary for formation of the altered host membranes required for HCV replication. This proposal describes a 5 year mentored training program to acquire further technical skills in the fields of molecular virology, phosphoinositides and cell trafficking, and cell imaging. These skills will be used to develop novel model systems to study the formation and composition of the HCV replication complex and its associated host membranes and proteins. The specific aims of this project are (1) to characterize the specificity of PI4KA inhibition for suppression of HCV replication, (2) to characterize the role of PI4KA through the viral replication cycle, and (3) to develop systems to study HCV replication complex assembly and composition. Although the specific aims are directed towards PI4KA, the systems and techniques to be developed during the award period will be applied to the study of other host cofactors of HCV replication. The proposed research will have direct public health benefits as a better understanding of the mechanisms that underline HCV replication complex assembly may lead to novel targets for HCV therapies. A better understanding of the HCV-host relationship is a stated goal of the NIH Action Plan for Liver Disease Research (Goal B2a). We have recently performed a whole-genome screen for human (host) proteins that are required by the hepatitis C virus for its replication. Such proteins are potential targets for new therapies for HCV. This proposal describes a 5-year research plan focusing on developing new systems to study how host cofactors direct the assembly of HCV replication complexes.

描述（由申请人提供）：慢性丙型肝炎病毒（HCV）感染在70-80％的暴露个人中发展，并影响全球3％的人口。需要更有效，更耐受的HCV疗法。我们的长期目标是定义宿主-HCV分子相互作用，并在这样做时确定新型的HCV治疗剂。我们已经完成了使用全基因组siRNA库进行HCV复制的宿主辅助因子的功能基因组筛选。在众多新型宿主辅助因子中，有PI4KA，一种磷脂酰肌醇4-激酶（PI 4-激酶）。我们假设PI4KA对于形成HCV复制所需的改变的宿主膜是必需的。该提案描述了一项为期5年的指导培训计划，该计划在分子病毒学，磷酸肌醇和细胞运输以及细胞成像领域获得了进一步的技术技能。这些技能将用于开发新型模型系统，以研究HCV复制复合物及其相关宿主膜和蛋白质的形成和组成。该项目的具体目的是（1）表征PI4KA抑制抑制HCV复制的特异性，（2）以表征PI4KA通过病毒复制周期的作用，（3）开发系统以研究HCV复制复制复合复杂复制复合物。组装和组成。尽管具体目标是针对PI4KA的，但在奖励期间要开发的系统和技术将应用于对HCV复制的其他宿主辅助因子的研究。拟议的研究将具有直接的公共卫生益处，以更好地理解强调HCV复制复合组装的机制，可能会导致HCV疗法的新目标。对HCV-host关系的更好理解是NIH肝病研究计划的明确目标（目标B2A）。最近，我们为人类（宿主）蛋白进行了全基因组筛选，乙型肝炎病毒需要复制。这种蛋白质是HCV新疗法的潜在靶标。该建议描述了一项为期5年的研究计划，重点是开发新系统，以研究主机辅助因子如何指导HCV复制复合络合物的组装。