权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Crystal structures and mechanism of disease of the astrovirus capsid protein

星状病毒衣壳蛋白的晶体结构和致病机制

基本信息

批准号：
8299883
负责人：
Rebecca Michelle DuBois
金额：
$ 15.76万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-24 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299883
关键词：
Actins Affect Animal Model Antibodies Antiviral Agents Antiviral Therapy Astrovirus Binding Biochemistry Biology Birds C-terminal Capsid Capsid Proteins Cell Culture Techniques Cell Death Cell-Matrix Junction Cells Cellular biology Cherry - dietary Child Chronic Collaborations Complex Cytoskeleton Data Development Diarrhea Disease Drug Delivery Systems Drug Design Enterotoxins Epithelial Cells Evolution Goals Human Immunocompromised Host In Vitro Individual Infection Inflammation Insecta Interdisciplinary Study Intestines Knowledge Laboratories Lead Length Light Mammals Manuscripts Medical Molecular Mutation Pathogenesis Pathogenicity Permeability Preparation Property Protein Structural Homology Proteins Proteolysis Receptor Cell Recombinants Regulation Research Serotyping Site-Directed Mutagenesis Species Specificity Structure Systemic infection Tertiary Protein Structure Testing Tight Junctions Time Toxin Translational Research Vaccine Design Vaccines Viral Virus-like particle Work X-Ray Crystallography base in vivo inhibitor/antagonist mutant nanoparticle novel programs public health relevance receptor receptor binding research study small molecule structural biology virology

项目摘要

DESCRIPTION (provided by applicant): Astroviruses are a leading cause of viral diarrhea in young children and can be associated with chronic diarrhea and even systemic infection in immunocompromised children. Vaccines and antiviral therapies for astrovirus infection are unavailable. In spite of their medical importance, the mechanism of astrovirus-induced disease is unknown. Recently, the laboratory of my collaborator, Dr. Stacey Schultz-Cherry, demonstrated for the first time that the astrovirus capsid protein alone induced diarrhea in an animal model suggesting that it functions as a novel viral enterotoxin (manuscript in preparation). In vitro and in vivo studies showed that the capsid protein induced diarrhea by increasing the permeability of intestinal epithelial cells by reorganizing the actin cytoskeleton and opening the cellular tight junctions. A fundamental gap in our knowledge is the structure of this unique viral enterotoxin. This information will not only lead to targeted antiviral approaches but may aid in the identification of other structurally similar proteins with toxin-like properties The goals of my research are to determine the structures and mechanism of disease of the astrovirus capsid protein. Further, I will identify the toxigenic domain and determine the structural basis for astrovirus antigenicity and species specificity. I will combine my expertise i structural biology and Dr. Schultz-Cherry's expertise with astrovirus biology to take a coordinated and hypothesis-driven approach to investigate the molecular mechanisms of astrovirus entry and pathogenesis by the capsid protein. We are uniquely suited to undertake these studies given our combined expertise in structural biology, biochemistry, cell biology, and virology leading to an interdisciplinary research program that will reveal the mechanism of astrovirus entry and pathogenesis. Furthermore, this work will be the basis for translational research in vaccine design, antiviral drug design, and development of astrovirus as a nanoparticle drug delivery vehicle.

描述(申请人提供)：星状病毒是幼儿病毒性腹泻的主要原因，可与免疫功能低下儿童的慢性腹泻甚至全身感染有关。目前还没有针对星状病毒感染的疫苗和抗病毒疗法。尽管它们在医学上很重要，但星状病毒引起的疾病的机制尚不清楚。最近，我的合作者Stacey Schultz-Cherry博士的实验室首次在动物模型中证明了星状病毒衣壳蛋白单独引起腹泻，这表明它是一种新的病毒肠毒素(手稿正在准备中)。体外和体内研究表明，衣壳蛋白通过重组肌动蛋白细胞骨架，开放细胞紧密连接，增加肠上皮细胞的通透性，从而导致腹泻。我们知识中的一个根本差距是这种独特的病毒肠毒素的结构。这些信息不仅将导致有针对性的抗病毒方法但可能有助于鉴定其他结构相似的具有毒素样特性的蛋白质。本研究的目的是确定星状病毒衣壳蛋白的结构和致病机制。此外，我将鉴定毒素结构域，并确定星状病毒抗原性和物种特异性的结构基础。我将结合我的结构生物学专业知识和舒尔茨-切里博士在星状病毒生物学方面的专业知识，采取一种协调的、以假设为导向的方法来研究星状病毒进入和衣壳蛋白致病的分子机制。鉴于我们在结构生物学、生物化学、细胞生物学和病毒学方面的综合专业知识，我们非常适合进行这些研究，从而形成一个跨学科的研究计划，揭示星状病毒进入和发病的机制。此外，这项工作将成为疫苗设计、抗病毒药物设计以及开发星状病毒作为纳米药物输送载体的翻译研究的基础。