Hepatitis delta virus RNA editing

丁型肝炎病毒RNA编辑

• 批准号: 6680126
• 负责人: JOHN L CASEY
• 金额: $ 13.25万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680126
• 关键词: RNA binding protein; RNA biosynthesis; adenosine deaminase; clinical research; flow cytometry; gene expression; genetic mapping; genotype; hepatitis D; hepatitis D virus; intermolecular interaction; nucleic acid structure; polymerase chain reaction; posttranscriptional RNA processing; protein structure; site directed mutagenesis; tissue /cell culture; transfection; virus RNA; virus antigen; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): Hepatitis delta virus (HDV) is a unique human pathogen that serves as an important model system for both virology and RNA biology. The goal in this proposal is to understand the mechanisms by which HDV RNA and protein structures regulate the specific editing of HDV RNA by a host adenosine deaminase, ADAR1. Understanding these mechanisms will provide a basis for advancing our understanding of HDV replication and pathogenesis, as well as RNA editing via adenosine deamination, which is increasingly recognized as an important post-transcriptional regulatory mechanism for both cellular and viral genes. HDV uses editing to extend the reading frame of the viral protein to make a form, HDAg-L, which both forms virus particles for secretion and inhibits viral RNA replication. Thus, RNA editing at the viral amber/W site plays a central role in the HDV replication cycle. The RNA sequences and structures required for editing, and the sequences added to HDAg-L that are essential for its packaging and inhibitory functions, are distinguishing features of the three HDV genotypes. We propose that comparative analysis of editing and HDAg-L function among the three HDV genotypes will provide valuable insight into the mechanisms by which HDV controls editing, and the relationship between editing levels and the role of HDAg-L in the HDV replication cycle. Because of the central role if editing in the HDV life cycle, this analysis is also likely to provide critical insights into the mechanistic basis for pathogenic variations among the HDV genotypes. The specific aims are: 1) to determine the contributions of different RNA structural elements to editing HDV RNA at the amber/W site in the three HDV genotypes; 2) determine the role and mechanism of RNA structural dynamics in HDV genotype III RNA editing and replication; 3) to determine the different mechanisms by which RNA editing is regulated in HDV genotypes I and III; and 4) to compare and contrast the functional properties of the viral protein HDAg-L in packaging and replication of HDV genotypes I and III.

描述（由申请人提供）：乙型肝炎病毒（HDV）是一种独特的人类病原体，是病毒学和RNA生物学的重要模型系统。该建议的目标是了解HDV RNA和蛋白质结构通过宿主腺苷脱氨酶ADAR1调节HDV RNA的特定编辑的机制。了解这些机制将为我们了解我们对HDV复制和发病机理的理解，以及通过腺苷脱氨基编辑的理解，这越来越多地被认为是细胞和病毒基因的重要后调节机制。 HDV使用编辑来扩展病毒蛋白的阅读框，形成一种形式的HDAG-L，这两者都形成了用于分泌的病毒颗粒并抑制病毒RNA的复制。因此，在病毒琥珀/W位点进行的RNA编辑在HDV复制周期中起着核心作用。编辑所需的RNA序列和结构，以及添加到HDAG-L中的序列，对于其包装和抑制功能至关重要，它区分了三种HDV基因型的特征。我们建议，在三种HDV基因型中对编辑和HDAG-L功能的比较分析将为HDV控制编辑的机制以及编辑水平与HDAG-L在HDV复制周期中的作用之间的关系提供宝贵的见解。由于在HDV生命周期中编辑的核心作用，因此该分析还可能为HDV基因型中致病性变异的机械基础提供关键见解。具体目的是：1）确定不同RNA结构元素对在三种HDV基因型中琥珀/W位点编辑HDV RNA的贡献； 2）确定RNA结构动力学在HDV基因型III RNA编辑和复制中的作用和机制； 3）确定在HDV基因型I和III中调节RNA编辑的不同机制； 4）在HDV基因型I和III的包装和复制中比较和对比病毒蛋白HDAG-L的功能特性。