Molecular Dissection of Norovirus Replication and Pathogenesis to Develop Therapeutics

 描述(由申请人提供)： 诺如病毒复制和发病机制的分子解剖以开发治疗项目概述诺如病毒是美国胃肠炎的最常见原因，它们给人们造成了巨大的经济和健康负担。控制人类诺如病毒感染的关键障碍包括无法在体外培养它们，以及缺乏预防或治疗人类诺如病毒感染的特定疗法。该计划项目的重点是建立在以前的基础科学和翻译发现和发现的基础上，使我们对这些病毒的生物学和发病机制的理解继续取得进展，从而可以开发出改进的控制策略。我们将在三个不同的项目中开展这些活动。在项目1中，我们进行的研究旨在为我们提供基本的分子理解，以了解人类对诺如病毒感染的免疫反应，以及影响病毒发病机制和毒株出现的因素。此外，我们将开展研究，制定可应用于高危人群的治疗和预防战略。在项目2中，我们将确定限制人类细胞复制的基础，总体目标是开发体外培养方法。我们还将评估诺如病毒蛋白表达调节细胞先天反应的分子机制，以及这些细胞反应是否调节病毒的复制和传播。在项目3中，我们将确定调节病毒复制和病毒-宿主相互作用的关键蛋白质的新功能的结构基础。这些项目将得到三个核心的支持。核心A(行政核心)将提供集中的行政和财政管理支助，并将协调方案活动。CORE B(显微镜和流式细胞术核心)将为每个与电子显微镜、荧光显微镜和流式细胞术相关的项目提供专业知识和服务。核心C(蛋白质和小分子化学核心)将为所有项目提供获得纯化蛋白质和病毒样颗粒的途径，以及促进所需的定点突变活动。此外，Core还将合成小分子，用于每个项目中的蛋白酶抑制研究。该计划项目汇集了一个高度合作的调查小组，他们拥有不同的技能和才华。与上一个供资期间一样，每个项目和每个核心之间的互动将是广泛的，因此每个项目的活动将大大加强，而不是如果项目独立进行所能取得的成果。

 DESCRIPTION (provided by applicant): Molecular Dissection of Norovirus Replication and Pathogenesis 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. Critical barriers to controlling human Norovirus infection include the inability to cultivate them in vitro and the lack of specific therapies available to prevent or treat human Norovirus infections. 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 will pursue these activities in three separate projects. In Project 1 we perform studies designed to provide us with a fundamental molecular understanding of the human immune response to Norovirus infection and that influences viral pathogenesis and strain emergence. In addition, we will perform studies to develop treatment and prevention strategies that can be applied to at risk populations. In Project 2 we will determine the basis of restriction to replication in human cells with the overall goal of developing in vitro cultivation methods. We will also evaluate molecular mechanisms by which Norovirus protein expression 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. 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 Flow Cytometry Core) will provide expertise and services to each project related to electron microscopy, fluorescent microscopy and flow cytometry. 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 facilitatng site-directed mutagenesis activities needed. In addition, the Core will synthesize small molecules to be used for protease inhibition studies in each project. The program project brings together a highly collaborative group of investigators with diverse skills and talents. As in the previous funding period, the interactions among each project and each of the cores will be extensive such that the activities of each project will be enhanced considerably over what could be accomplished if the projects were pursued independently.