Crystal structures and mechanism of disease of the astrovirus capsid protein

描述（由申请方提供）：星状病毒是幼儿病毒性腹泻的主要原因，可能与免疫功能低下儿童的慢性腹泻甚至全身感染有关。星状病毒感染的疫苗和抗病毒疗法是不可用的。尽管它们在医学上很重要，但星状病毒引起疾病的机制尚不清楚。最近，我的合作者Stacey Schultz-Cherry博士的实验室首次证明，单独的星状病毒衣壳蛋白在动物模型中诱导腹泻，表明它作为一种新型病毒肠毒素发挥作用（手稿正在编写中）。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和打开细胞紧密连接来增加肠上皮细胞的通透性，从而诱导腹泻。我们知识的一个根本空白是这种独特的病毒肠毒素的结构。这一信息不仅将导致有针对性的抗病毒方法 但可能有助于鉴定具有毒素样性质的其他结构相似的蛋白质。我的研究目标是确定星状病毒衣壳蛋白的结构和疾病机制。此外，我将确定的基因结构域，并确定星状病毒抗原性和种属特异性的结构基础。我将联合收割机结合我在结构生物学方面的专业知识和Schultz-Cherry博士在星状病毒生物学方面的专业知识，采取协调和假设驱动的方法来研究星状病毒衣壳蛋白进入和致病的分子机制。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一个跨学科的研究计划，将揭示星状病毒进入和发病机制的机制。此外，这项工作将成为疫苗设计、抗病毒药物设计和星状病毒作为纳米颗粒药物递送载体的开发的转化研究的基础。

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.