Picornavirus-host Cell Interactions and Disease

小核糖核酸病毒-宿主细胞相互作用和疾病

• 批准号: 7354760
• 负责人: RAYMOND Philip ROOS
• 金额: $ 33.44万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-20 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354760
• 关键词: 5' Untranslated Regions; Affect; Binding; Binding Proteins; Cardiovirus; Cell Communication; Cells; Chronic; Complex; Data; Demyelinations; Disease; Enterovirus; Family Picornaviridae; Gene Expression; Human poliovirus; Inflammatory; Internal Ribosome Entry Site; Learning; Neurons; Phenotype; Polioviruses; Polyproteins; Protein Binding; Proteins; Publishing; RNA-Binding Proteins; Site; Subgroup; TMEV; Translation Initiation; Translational Regulation; Translations; Untranslated Regions; Virus; attenuation; cell type; disease phenotype; interest; member; neurovirulence; pathogen; viral RNA; virus pathogenesis

DESCRIPTION (provided by applicant): The pathogenesis of virus-induced disease is complex with many host-, cell-, and pathogen specific determinants. A general theme of this proposal is the importance of viral RNA translational regulation and cell-type specific RNA binding proteins in determining picornavirus-induced disease. Our studies involve Theiler's murine encephalomyelitis virus (TMEV), a member of the cardiovirus genus, and poliovirus (PV), a member of the enterovirus genus. Our main interests in this proposal are: neural cell type-specific proteins which bind to the internal ribosome entry site (IRES) of the 5'- untranslated region (UTR), and thereby regulate the efficiency of translation initiation and affect TMEV or PV neurovirulence; preferential translation of an alternatively initiated protein of TMEV called L* (a protein synthesized from an alternative translation initiation site that is out of frame with the polyprotein, a unique finding among picornaviruses), that is important in virus persistence and demyelination of DA strain of TMEV. This proposal: reviews and extends our published data demonstrating that the presence of cell type-specific proteins that bind the internal ribosome entry site (IRES) of the 5'-UTR of GDVII strain of TMEV are key in regulating viral RNA translation and neurovirulence; provides recent data indicating the importance of cell type-specific IRES-binding proteins in the attenuation of Sabin strain of PV3; focuses on the importance of L* in determining the remarkable phenotype of DA strain and other TO subgroup strains of TMEV (i.e., virus persistence and chronic inflammatory demyelination). The data and approaches that are leaned in this proposal are applicable to our understanding of neurotrophic viruses more broadly. The specific aims are: 1) To identify determinants in the TMEV and PV 5'UTRs that regulate translation and affect disease phenotype, and clarify their mechanisms of action 2) To: a) identify the effect of cell type on the expression of TMEV L*, and b) determine the effect of TMEV gene expression on the cell.

描述(由申请人提供)：病毒引起的疾病的发病机制是复杂的，有许多宿主、细胞和病原体特定的决定因素。这项建议的一个总主题是病毒RNA翻译调节和细胞类型特异性RNA结合蛋白在确定小核糖核酸病毒诱导的疾病中的重要性。我们的研究涉及泰勒氏小鼠脑脊髓炎病毒(TMEV)，心脏病毒属的成员，以及脊髓灰质炎病毒(PV)，肠病毒属的成员。我们对这一建议的主要兴趣是：神经细胞类型特异的蛋白质，它与5‘-非翻译区的内部核糖体进入位点(IRES)结合，从而调节翻译起始的效率，从而影响TMEV或PV的神经毒力；优先翻译TMEV的另一种可选起始蛋白L*(从另一个与多聚蛋白不同的翻译起始点合成的蛋白质，这在微小核糖核酸病毒中是独一无二的)，这在TMEV DA株的病毒持久性和脱髓鞘中是重要的。这项建议：回顾和扩展我们发表的数据，证明存在与TMEV GDVII株5‘-UTRIRES结合的细胞类型特异性蛋白是调控病毒RNA翻译和神经毒力的关键；提供了最新数据表明细胞类型特异性IRES结合蛋白在PV3Sabin株减毒中的重要性；重点关注L*在确定DA株和其他TMEV亚型株的显著表型(即病毒持久性和慢性炎性脱髓鞘)中的重要性。这项建议中倾向的数据和方法适用于我们对神经营养病毒的更广泛的理解。具体目的是：1)确定TMEV和PV5‘UTRs中调节翻译和影响疾病表型的决定因素，并阐明它们的作用机制 2)确定细胞类型对TMEV L基因表达的影响，以及确定TMEV基因表达对细胞的影响。