Metabolomics of the Virus-host Cell Interaction

病毒-宿主细胞相互作用的代谢组学

基本信息

批准号：
7900055
负责人：
JOSHUA D RABINOWITZ
金额：
$ 30.96万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900055
关键词：
A549 Acquired Immunodeficiency Syndrome Acute Amino Acids Antiviral Agents Antiviral Therapy Arts Avian Influenza Bayesian Analysis Biochemical Biochemical Pathway Biological Cancer Etiology Cell Communication Cell Line Cell Survival Cells Cellular Structures Characteristics Chronic Cluster Analysis Common Cold Communicable Diseases Communities Computer Simulation Critical Pathways Cytomegalovirus Data Data Analyses Data Files Data Set Databases Disease Drug usage Elements Environment Epithelial Feedback Fibroblasts Future Genes Genomics Glucose Grant Growth HIV Hepatitis B Herpes Simplex Infections Herpesviridae Herpesvirus 1 Housing Human Human Virus Imagery Immune response Individual Infection Influenza Isotope Labeling Knock-out Knowledge Lead Light Link Liquid Chromatography Literature Lung Maintenance Maps Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Mining Modeling Molecular Normal Range Nucleic Acids Nucleosides Nutrient Output Parasites Pathway interactions Phenotype Platelet-Derived Growth Factor Positioning Attribute Property Public Health RNA RNA Interference Regulation Reliance Research Research Infrastructure Research Personnel Rhinovirus Sampling Signal Transduction Simplexvirus Solid Source Systems Biology Techniques Technology Testing Transcript United States Viral Viral Genes Virus Virus Diseases base cell type data modeling database design drug development environmental change human disease latent infection macromolecule metabolomics neoplastic cell novel pathogen programs research study response small molecule tandem mass spectrometry trend virus identification web-accessible

A549 Acquired Immunodeficiency Syndrome Acute Amino Acids Antiviral Agents Antiviral Therapy Arts Avian Influenza Bayesian Analysis Biochemical Biochemical Pathway Biological Cancer Etiology Cell Communication Cell Line Cell Survival Cells Cellular Structures Characteristics Chronic Cluster Analysis Common Cold Communicable Diseases Communities Computer Simulation Critical Pathways Cytomegalovirus Data Data Analyses Data Files Data Set Databases Disease Drug usage Elements Environment Epithelial Feedback Fibroblasts Future Genes Genomics Glucose Grant Growth HIV Hepatitis B Herpes Simplex Infections Herpesviridae Herpesvirus 1 Housing Human Human Virus Imagery Immune response Individual Infection Influenza Isotope Labeling Knock-out Knowledge Lead Light Link Liquid Chromatography Literature Lung Maintenance Maps Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Mining Modeling Molecular Normal Range Nucleic Acids Nucleosides Nutrient Output Parasites Pathway interactions Phenotype Platelet-Derived Growth Factor Positioning Attribute Property Public Health RNA RNA Interference Regulation Reliance Research Research Infrastructure Research Personnel Rhinovirus Sampling Signal Transduction Simplexvirus Solid Source Systems Biology Techniques Technology Testing Transcript United States Viral Viral Genes Virus Virus Diseases base cell type data modeling database design drug development environmental change human disease latent infection macromolecule metabolomics neoplastic cell novel pathogen programs research study response small molecule tandem mass spectrometry trend virus identification web-accessible

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项目摘要

DESCRIPTION (provided by applicant): Viruses are parasites. They depend on the metabolic network of the host cell to provide the energy and macromolecule subunits necessary for their replication. In preliminary experiments we have found that infection of human fibroblasts with cytomegalovirus produces dramatic metabolome alterations, highlighting the importance of virus-host metabolic interactions. Despite this recent progress, the effect of viruses on host cell metabolism remains little understood. Here we propose to combine state-of-the art metabolomic, genomic, and Bayesian modeling techniques to revolutionize understanding of virus-host metabolic interactions. Three different viruses, each important human pathogens, will be investigated: influenza A, herpes simplex, and cytomegalovirus. The dynamic metabolic changes that occur upon normal modulation of the host cell environment (e.g., with nutrients) will be compared to those that occur upon viral infection, using liquid chromatography-tandem mass spectrometry to quantitate 100+ metabolites and microarrays to measure the complete transcriptional response. The resulting data will be stored in a publicly accessible database and analyzed by clustering and decomposition techniques to identify major trends in the data, e.g., metabolic effects that are common across all of the viruses. Bayesian analysis will then be used to identify functional interactions between viral infection, metabolites, and genes. The predictive power of the resulting models will be tested through model-guided experiments, involving, for example, viral gene knockouts or inhibition of specific host cell metabolic pathways. Successful completion of this research will dramatically advance overall biological knowledge of pathogen-host metabolic interactions, with a specific focus on viruses, the most important and least treatable causes of infectious disease in the United States. Relevance: Viruses cause diseases ranging from the common cold to influenza to AIDS. In all cases, for the viruses to survive and grow, they must acquire energy and biochemical building blocks from the cells that they infect. We aim to apply a mixture of advanced measurement technologies and computational modeling to determine the pathways that viruses use to trick the infected host cells into making the materials they need. Such pathways, once identified, will be attractive new targets for antiviral therapy.

描述（申请人提供）：病毒是寄生虫。它们取决于宿主细胞的代谢网络，以提供复制所需的能量和大分子亚基。在初步实验中，我们发现人类成纤维细胞的感染具有巨细胞病毒会产生戏剧性的代谢组改变，突显了病毒宿主代谢相互作用的重要性。尽管取得了最近的进展，但病毒对宿主细胞代谢的影响仍未了解。在这里，我们建议将最新的代谢组，基因组和贝叶斯建模技术结合起来，以彻底改变人们对病毒宿主代谢相互作用的理解。将研究三种不同的病毒，每种病毒：流感，单纯疱疹和巨细胞病毒。使用液相色谱量表质谱法对宿主细胞环境的正常调节（例如，用营养素）进行正常调节（例如，用营养素）进行的动态代谢变化将进行比较，以定量100+代谢物和微阵列，以测量完整的转录反应。所得数据将存储在可公开访问的数据库中，并通过聚类和分解技术进行分析，以识别数据中的主要趋势，例如所有病毒中常见的代谢效应。然后，贝叶斯分析将用于鉴定病毒感染，代谢产物和基因之间的功能相互作用。所得模型的预测能力将通过模型引导的实验进行测试，涉及病毒基因敲除或抑制特定宿主细胞代谢途径。这项研究的成功完成将极大地提高病原体宿主代谢相互作用的总体生物学知识，并特别关注病毒，这是美国传染病最重要，最不可治疗的原因。相关性：病毒引起的疾病，从普通感冒到流感到艾滋病。在所有情况下，要使病毒生存和生长，它们必须从其感染的细胞中获取能量和生化构件。我们的目的是应用高级测量技术和计算建模的混合物，以确定病毒用来欺骗感染宿主细胞制造所需材料的途径。曾经确定的这种途径将是抗病毒治疗的有吸引力的新靶标。