Mechanisms of Norovirus Pathogenesis and Replication to Develop Therapeutics

诺如病毒发病机制和复制机制以开发治疗方法

• 批准号: 10450701
• 负责人: Robert L. Atmar
• 金额: $ 217.45万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450701
• 关键词: Acute; Address; Antibodies; Antibody Response; Antiviral Agents; Basic Science; Biological Assay; Biology; Biosensor; Cell Culture System; Cells; Chemistry; Clinical; Collaborations; Complement; Cryoelectron Microscopy; Crystallography; Data; Development; Disease; Economics; Electron Microscopy; Epitopes; Evaluation; Funding; Gastroenteritis; Goals; Health; Human; Immunity; In Vitro; Infection; Infection prevention; Intestines; Knowledge; Mediating; Microscopy; Modeling; Molecular; Norovirus; Pathogenesis; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Polymerase; Population; Populations at Risk; Prevention strategy; Proteins; Public Health; RNA Polymerase III; RNA-Directed RNA Polymerase; Receptor Cell; Recording of previous events; Regimen; Reproducibility; Research; Research Design; Research Personnel; Role; Services; Site-Directed Mutagenesis; Structure; Symptoms; Synthesis Chemistry; System; Talents; Testing; Therapeutic; United States; Vaccines; Viral; Viral Antibodies; Viral Pathogenesis; Viral Physiology; Viral Proteins; Virus; Virus Replication; Virus-like particle; antiviral drug development; base; biophysical techniques; combat; cross reactivity; design; effective therapy; experience; helicase; human stem cells; improved; inhibitor; insight; neutralizing antibody; novel; pathogen; programs; prospective; receptor; response; skills; small molecule; success; therapeutically effective; treatment strategy; virus host interaction

Mechanisms of Norovirus Pathogenesis and Replication to Develop Therapeutics Project Summary Noroviruses are the most common cause of gastroenteritis in the United States, and they cause a significant economic and health burden to the population. A significant barrier to progress in making effective therapeutics, antivirals and vaccines to control human norovirus illness was the previous lack of a cell culture system. The focus of this program project is to build upon previous basic science and translational findings and discoveries to allow continued progress in our understanding of the biology and pathogenesis of these viruses so that improved control strategies can be developed. We recently developed a successful replication system that discovered strain- specific requirements for replication and allows neutralization assays and antivirals to be tested. We will pursue key questions on virus pathogenesis and cellular responses, structure-function studies on the interactions between virus proteins and host components, discover key factors that restrict extensive propagation and test antivirals and neutralizing antibodies in three separate projects. In Project 1 we will perform studies designed to provide us with a fundamental molecular understanding of how human noroviruses cause disease, and of what epitopes are recognized by human sera that are associated with virus neutralization, virus clearance, and protective immunity. In addition, we will build on recent success and continue to develop antivirals for treatment and prevention strategies that can be applied to at risk populations. In Project 2 we will continue to improve the cultivation system, focusing on identifying the cell receptor(s) and understanding why all HuNoV strains do not grow in the replication system. We will also evaluate molecular mechanisms by which norovirus replication regulates cellular innate responses and whether these cellular responses regulate viral replication and spread. In Project 3 we will determine the structural basis for novel functions of key proteins that regulate viral replication and virus-host interactions to provide a rational framework for the development of antivirals. These projects will be supported by three cores. Core A (Administrative Core) will provide centralized administrative and fiscal management support and will coordinate programmatic activities. Core B (the Microscopy and Enteroid Core) will provide expertise and services to each project related to electron microscopy and fluorescent microscopy. This core will also maintain and provide enteroids, including genetically-modified cultures and biosensor lines to all projects. Core C (the Protein and Small Molecule Chemistry Core) will provide all projects with access to purified proteins and virus-like particles as well as facilitating site-directed mutagenesis activities needed. In addition, the Core will synthesize small molecules to be used for protease and polymerase inhibition studies in each project. The program project brings together a highly collaborative group of investigators with diverse skills and talents, and an substantial history of working together. As in the previous funding period, the interactions among each project and each of the cores will be extensive and synergistic such that the activities of each project will be enhanced considerably over what could be accomplished if the projects were pursued independently.

诺如病毒发病机制和复制机制以开发治疗方法 项目概要 诺如病毒是美国胃肠炎最常见的原因，它们会导致严重的胃肠炎。 给人民带来经济和健康负担。取得有效治疗进展的一个重大障碍， 控制人类诺如病毒疾病的抗病毒药物和疫苗是以前缺乏细胞培养系统的。焦点 该计划项目的目的是建立在以前的基础科学和转化研究结果和发现的基础上 我们对这些病毒的生物学和发病机制的了解不断取得进展，从而改善了 可以制定控制策略。我们最近开发了一个成功的复制系统，发现了菌株- 复制的特定要求，并允许测试中和测定和抗病毒药物。我们将追求关键 关于病毒发病机制和细胞反应的问题，关于病毒之间相互作用的结构功能研究 病毒蛋白和宿主成分，发现限制广泛传播的关键因素并测试抗病毒药物 以及三个独立项目中的中和抗体。在项目 1 中，我们将进行旨在提供 我们对人类诺如病毒如何引起疾病以及哪些表位有基本的分子了解 被人类血清识别，与病毒中和、病毒清除和保护相关 免疫。此外，我们将在最近的成功基础上继续开发用于治疗和预防的抗病毒药物 可应用于高危人群的策略。项目2我们将继续完善种植体系， 专注于识别细胞受体并了解为什么所有 HuNoV 毒株在复制中不生长 系统。我们还将评估诺如病毒复制调节细胞先天性的分子机制 反应以及这些细胞反应是否调节病毒复制和传播。在项目 3 中，我们将 确定调节病毒复制和病毒宿主的关键蛋白新功能的结构基础 相互作用，为抗病毒药物的开发提供合理的框架。这些项目将得到支持 由三个核心。核心A（行政核心）将提供集中的行政和财务管理 支持并协调计划活动。核心 B（显微镜和 Enteroid 核心）将提供 与电子显微镜和荧光显微镜相关的每个项目的专业知识和服务。该核心将 还为所有项目维护和提供肠类，包括转基因培养物和生物传感器系列。 Core C（蛋白质和小分子化学核心）将为所有项目提供纯化蛋白质的途径 和病毒样颗粒以及促进所需的定点诱变活动。此外，核心将 合成小分子用于每个项目中的蛋白酶和聚合酶抑制研究。该计划 该项目汇集了一群高度协作的研究人员，他们具有不同的技能和才能，并且 丰富的合作历史。与之前的资助期一样，每个项目之间的相互作用 每个核心都将具有广泛性和协同性，从而加强每个项目的活动 大大超过了如果这些项目独立进行的话可以完成的事情。