Protein homeostasis mechanisms underlying enterovirus replication and evolution

肠道病毒复制和进化的蛋白质稳态机制

基本信息

批准号：
8300826
负责人：
Raul Andino
金额：
$ 194.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-13 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300826
关键词：
Affinity Attenuated Bioinformatics Biological Cells Collaborations Coxsackie Viruses Data Data Set Dependency Development Disease Enterovirus Enterovirus 71 Evolution Failure Genetic Homeostasis Human Human poliovirus Imagery Infection Institutes Integration Host Factors Lead Life Link Maps Mass Spectrum Analysis Methodology Methods Molecular Molecular Chaperones Monitor Mutation Pathogenesis Pathway interactions Pharmaceutical Preparations Poliomyelitis Polioviruses Population Post-Translational Protein Processing Prevention Process Production Proteins Proteomics Quality Control RNA Interference Research Role Surveys Syndrome System Technology Testing Therapeutic Intervention Ubiquitination Vaccines Viral Virus Work base design drug resistant virus follow-up functional genomics interest multidisciplinary novel novel strategies pathogen protein complex protein degradation protein function protein protein interaction tool virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The focus of this proposal is to dissect the role of Protein Homeostasis in enterovirus replication, evolution and pathogenesis. The paradigm for these studies is that enteroviruses are highly dependent on the cellular chaperone and quality control (QC) machinery for their protein production and function. Furthermore, given the very high mutation rates of these viruses, we hypothesize that the chaperones and QC network is key to modulating virus diversity, evolution and pathogenesis. We propose to examine how host protein homeostasis machinery participates in enterovirus replication and modulates viral diversity and how viruses use this machinery to alleviate the detrimental effect of mutations that accumulate during replication. We have recently demonstrated that high mutation rate of enteroviruses is essential for their adaptability and pathogenesis. Thus, restricting viral diversity through the modulation of protein homeostasis machinery could provide powerful ways to attenuate virus pathogenesis. This proposal combines computational, cell biological, molecular and systems approaches to define the host protein homeostasis network involved in enteroviral replication and determine the role of this network to viral evolution, diversity, and pathogenesis. These new approaches are essential given the failure of traditional strategies to achieve any therapeutic intervention against enteroviruses (such as polio, coxsackie, and enterovirus 71) and it has the potential to set the basis for the prevention of current and emerging enteroviral diseases . This proposal describes a multidisciplinary and highly integrated approach that is designed to obtain this critically important information. We propose 3 Specific Projects and 2 Cores: Project 1: Host-enterovirus circuitry revealed by global analysis of cellular networks; Project 2: Role of cellular factors in enterovirus protein homeostasis and function; and Project 3: Role of protein homeostasis in enterovirus population diversity, evolution and pathogenesis. Core A: Administrative Core; and Core B: "High-throughput functional genomics and proteomics core.

描述（由申请人提供）：该建议的重点是剖析蛋白质稳态在肠病毒复制，进化和发病机理中的作用。这些研究的范例是，肠病毒高度依赖于细胞伴侣和质量控制（QC）机械的蛋白质产生和功能。此外，鉴于这些病毒的突变速率非常高，我们假设伴侣和QC网络是调节病毒多样性，进化和发病机理的关键。我们建议研究宿主蛋白稳态机制如何参与肠病毒复制，调节病毒多样性，以及病毒如何使用这种机械来减轻复制过程中积累的突变的有害效应。我们最近证明，肠病毒的高突变率对于它们的适应性和发病机理至关重要。因此，通过调节蛋白质稳态机制来限制病毒多样性可以提供强大的方法来减轻病毒发病机理。该建议结合了计算，细胞生物学，分子和系统方法来定义参与肠病毒复制的宿主蛋白稳态网络，并确定该网络对病毒进化，多样性和发病机理的作用。鉴于传统策略未能实现针对肠内病毒（例如脊髓灰质炎，Coxsackie和肠病毒71）的任何治疗性干预措施，因此这些新方法至关重要，并且它有可能为预防当前和新兴的肠病毒疾病的预防奠定基础。该提案描述了一种多学科和高度综合的方法，旨在获取这一至关重要的信息。我们提出了3个特定的项目和2个核心：项目1：通过全球蜂窝网络分析揭示的宿主 - 进入病毒电路；项目2：细胞因子在肠病毒蛋白稳态和功能中的作用；和项目3：蛋白稳态在肠病毒种群多样性，进化和发病机理中的作用。核心A：行政核心；和核心B：“高通量功能基因组学和蛋白质组学核心。