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（由申请人提供）：果毒病毒是幼儿病毒性腹泻的主要原因，可以与免疫功能低下的儿童有关慢性腹泻甚至全身感染有关。甲壳虫感染的疫苗和抗病毒疗法不可用。尽管具有医学重要性，但尚不清楚呈甲状腺病毒引起的疾病的机制。最近，我的合作者的实验室Stacey Schultz-Cherry博士首次证明了Astrovirus Capsid蛋白在动物模型中诱导腹泻，这表明它是一种新型病毒肠毒素（制备中的手稿）。体外和体内研究表明，衣壳蛋白通过重新组织肌动蛋白细胞骨架并打开细胞紧密连接来增加肠上皮细胞的渗透性来诱导腹泻。我们所知的根本差距是这种独特的病毒肠毒素的结构。这些信息不仅会导致针对性的抗病毒方法但是，可能有助于鉴定具有类似毒素的特性的其他结构相似的蛋白质，我的研究目标是确定星形病毒衣壳蛋白疾病的结构和机理。此外，我将确定毒素结构域，并确定星形病毒抗原性和物种特异性的结构基础。我将结合我的专业知识I结构生物学和Schultz-Cherry博士与Astrovirus Biology的专业知识，以采用一种协调的假设驱动的方法，以研究Capsid蛋白的分子机制和发病机理的分子机制。我们非常适合进行这些研究，因为我们在结构生物学，生物化学，细胞生物学和病毒学方面的综合专业知识，导致了跨学科研究计划，该计划将揭示Astrovirus进入和发病机理的机制。此外，这项工作将是疫苗设计，抗病毒药物设计和星期病毒作为纳米颗粒药物输送车的发展基础。