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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（由申请方提供）：无包膜二十面体病毒的外壳蛋白必须在病毒生命周期中发挥多种功能，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、与宿主受体相互作用以及拆卸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点，需要在分子水平上彻底了解多种衣壳特性。我们选择研究的系统是星状病毒，一个二十面体单链RNA病毒家族，是人类和动物胃肠炎的病原体。很少有人知道什么区域的外壳蛋白有助于不同的衣壳功能。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，装配和RNA包装功能的星状病毒外壳蛋白构成一个单独的，模块化的结构域，是不同的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，测试在生物学实验中是否表现出病毒体组装、颗粒成熟和RNA降解所需的外壳蛋白区域的功能预测。(2)通过构建星状病毒科不同血清型和种间的嵌合外壳蛋白分子来检测外壳蛋白“组装域”的模块性。这些研究的基本原理是，深入了解星状病毒组装，核酸包装，成熟和向性的分子机制将告知我们星状病毒外壳蛋白的独特和共享的特性。此外，工程化嵌合星状病毒颗粒的潜力，显示在颗粒表面上的特定表位可以有实际的应用，如基于颗粒的疫苗的产生。嵌合星状病毒颗粒展示相关胃肠炎病毒如诺如病毒（一种B类生物恐怖剂）的表面抗原，可被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加对星状病毒颗粒生物学的理解，而且还将导致治疗药物或疫苗的开发，以对抗人类的病毒性胃肠炎。