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: 8296579
• 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/8296579
• 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）： 70-80% 的接触者患有慢性丙型肝炎病毒 (HCV) 感染，影响世界人口的 3%。需要更有效和更好耐受的HCV疗法。我们的长期目标是确定宿主-HCV 分子相互作用，并在此过程中确定用于 HCV 治疗的新型治疗药物。我们已经使用全基因组 siRNA 文库完成了 HCV 复制宿主辅助因子的功能基因组筛选。在众多已鉴定的新型宿主辅助因子中，PI4KA 是一种磷脂酰肌醇 4-激酶（PI 4-激酶）。我们假设 PI4KA 对于 HCV 复制所需的改变的宿主膜的形成是必需的。该提案描述了一项为期 5 年的指导培训计划，旨在获得分子病毒学、磷酸肌醇和细胞运输以及细胞成像领域的进一步技术技能。这些技能将用于开发新的模型系统，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。该项目的具体目标是 (1) 表征 PI4KA 抑制对抑制 HCV 复制的特异性，(2) 表征 PI4KA 在病毒复制周期中的作用，以及 (3) 开发系统来研究 HCV 复制复合物组装和组成。尽管具体目标是针对 PI4KA，但奖励期间开发的系统和技术将应用于 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健康益处，因为更好地了解 HCV 复制复合体组装的机制可能会导致 HCV 治疗的新靶点。更好地了解 HCV-宿主关系是 NIH 肝病研究行动计划（目标 B2a）的既定目标。我们最近对丙型肝炎病毒复制所需的人类（宿主）蛋白质进行了全基因组筛选。这些蛋白质是丙型肝炎新疗法的潜在靶点。该提案描述了一项为期 5 年的研究计划，重点是开发新系统来研究宿主辅助因子如何指导 HCV 复制复合物的组装。

项目成果

A homogeneous and nonisotopic assay for phosphatidylinositol 4-kinases.

• DOI: 10.1016/j.ab.2011.05.046
• 发表时间: 2011-10-01
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: Tai AW;Bojjireddy N;Balla T
• 通讯作者: Balla T

Genetic and functional studies of phosphatidyl-inositol 4-kinase type IIIα.

磷脂酰肌醇4激酶IIIα型的遗传和功能研究。

• DOI: 10.1016/j.bbalip.2011.04.013
• 发表时间: 2011
• 期刊: Biochimica et biophysica acta
• 作者: Szentpetery,Zsofia;Szakacs,Gergely;Bojjireddy,Naveen;Tai,AndrewW;Balla,Tamas
• 通讯作者: Balla,Tamas

Oxysterol-binding protein is a phosphatidylinositol 4-kinase effector required for HCV replication membrane integrity and cholesterol trafficking.

• DOI: 10.1053/j.gastro.2014.02.002
• 发表时间: 2014-05
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Wang H;Perry JW;Lauring AS;Neddermann P;De Francesco R;Tai AW
• 通讯作者: Tai AW