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Molecular analysis of astrovirus capsid assembly

星状病毒衣壳组装的分子分析

基本信息

批准号：
6896181
负责人：
NEEL KUMAR KRISHNA
金额：
$ 17.6万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2007-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Coat proteins of non-enveloped, icosahedral viruses must perform a variety of functions during the virus life cycle, such as assembly of the coat protein subunits into a closed shell, specific encapsidation of the viral nucleic acid, maturation of the capsid, interaction with host receptors and disassembly to deliver the genetic information into the newly-infected cell. A thorough understanding of the multiple capsid properties at the molecular level is required in order to identify potent targets for antiviral therapy and the prevention of viral disease. The systems we have chosen for study are the astroviruses, a family of icosahedral, single-stranded RNA virus that is a causative agent of gastroenteritis in both humans and animals. Very little is known about what regions of the coat protein contribute to the diverse capsid functions. The objective of this application is to test whether novel structural predictions we have made based on the coat protein sequence of the human astroviruses are exhibited in biological experiments. We hypothesize that the assembly and RNA packaging functions of the astrovirus coat protein constitute an individual, modular domain that is distinct from the determinants required for receptor binding and internalization. Our specific aims are: (1) To test whether functional predictions of regions of the coat protein required for virion assembly, particle maturation, and RNA encapsidation are exhibited in biological experiments, by characterizing the phenotypes of a series of mutations. (2) To test the modularity of the coat protein "assembly domain" by constructing chimeric coat protein molecules between different serotypes and species of the Astroviridae. The rationale for these studies is that insight into the molecular mechanisms of astrovirus assembly, nucleic acid packaging, maturation and tropism will inform us of unique and shared properties of astrovirus coat proteins. In addition, the potential to engineer chimeric astrovirus particles that display specific epitopes on the surface of the particle could have practical applications such as generation of particle-based vaccines. Chimeric astrovirus particles displaying surface antigens of related gastroenteritis virus such as norovirus, a Category B bioterrorism agent, could be developed as a polyvalent, preventative vaccine. In the long term, we expect that this work will add not only to the understanding of astrovirus particle biology, but also lead to the development of therapeutic drugs or vaccines to combat viral gastroenteritis in humans.

描述（申请人提供）：无包膜二十面体病毒的外壳蛋白必须在病毒生命周期中执行多种功能，例如将外壳蛋白亚基组装成封闭的外壳、病毒核酸的特异性衣壳化、衣壳的成熟、与宿主受体的相互作用以及分解以将遗传信息传递到新感染的细胞中。为了确定抗病毒治疗和预防病毒性疾病的有效靶标，需要在分子水平上彻底了解衣壳的多种特性。我们选择用于研究的系统是星状病毒，它是二十面体单链RNA病毒家族，是人类和动物胃肠炎的病原体。关于外壳蛋白的哪些区域有助于衣壳的多种功能，人们知之甚少。本申请的目的是测试我们基于人类星状病毒外壳蛋白序列所做的新结构预测是否在生物实验中表现出来。我们假设星状病毒外壳蛋白的组装和 RNA 包装功能构成了一个单独的模块化结构域，该结构域不同于受体结合和内化所需的决定因素。我们的具体目标是：（1）通过表征一系列突变的表型，测试病毒粒子组装、颗粒成熟和RNA衣壳化所需的外壳蛋白区域的功能预测是否在生物实验中表现出来。 (2)通过构建星状病毒科不同血清型和物种之间的嵌合外壳蛋白分子来测试外壳蛋白“组装结构域”的模块化。这些研究的基本原理是，对星状病毒组装、核酸包装、成熟和向性的分子机制的深入了解将使我们了解星状病毒外壳蛋白的独特和共有的特性。此外，设计在颗粒表面显示特定表位的嵌合星状病毒颗粒的潜力可能具有实际应用，例如生成基于颗粒的疫苗。显示相关胃肠炎病毒（例如诺如病毒，一种 B 类生物恐怖主义制剂）表面抗原的嵌合星状病毒颗粒可以开发为多价预防性疫苗。从长远来看，我们预计这项工作不仅将增进对星状病毒颗粒生物学的理解，还将促进人类病毒性胃肠炎治疗药物或疫苗的开发。