Flavivirus non-coding RNAs and the Host mRNA Decay Machinery
黄病毒非编码 RNA 和宿主 mRNA 衰变机制
基本信息
- 批准号:9762831
- 负责人:
- 金额:$ 37.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-28 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated Regions5&apos Untranslated Regions5&apos-exoribonucleaseAntiviral TherapyBiologicalBovine Viral Diarrhea VirusesCatalogingCatalogsCell LineCellsCellular StructuresClinicalComplexCytopathologyDataDengue VirusDetectionDigestionDiseaseElementsEnzymesExonucleaseExoribonucleasesFamilyFeedbackFlaviviridaeFlavivirusFlavivirus InfectionsFoundationsGene ExpressionGene Expression ProcessGenetic TranscriptionGoalsHepatitis C virusHepatitis C-Like VirusesInfectionInsectaInternal Ribosome Entry SiteLaboratoriesMammalian CellMediatingMessenger RNAMicroRNAsMolecularNaturePathogenicityPathway interactionsPlayPoly AProcessPropertyPublishingQuality ControlRNARNA DecayRNA DegradationRNA VirusesRegulationRepressionRoleSeriesStructureTestingTranscriptTranscription Initiation SiteUntranslated RNAUntranslated RegionsViralViral PathogenesisVirusVirus ReplicationWest Nile virusWorkZika Viruscell growth regulationdesignexperimental studygenome-widehuman pathogeninhibitor/antagonistinsightmRNA DecaymRNA StabilitymRNA decappingmembernovelnovel strategiespathogenpoly A specific exoribonucleasepolyadenylated messenger RNAtranscriptometumorigenesisviral RNAvirus host interaction
项目摘要
The Flaviviridae are a family of positive-sense RNA viruses that contain numerous important human
pathogens. Many of the molecular mechanisms that underlie how these RNA viruses cause cytopathology
and disease are not clearly described. The cellular mRNA decay machinery, in particularly the 5'-3' pathway
mediated by the exoribonuclease Xrn1, plays a major role in regulating the abundance and quality of gene
expression in the cell. Understudied, but nevertheless very important aspects of flavivirus-host interactions,
include how viral RNAs are protected from degradation by the cellular mRNA decay machinery and what are
the implications of the viral RNA stabilization strategies on the regulation of cellular mRNA stability. We have
recently observed that flaviviruses repress the activity of Xrn1 through trapping the enzyme using unique
structured regions of the viral RNA. Interestingly, it is the 5' UTR IRES region that is responsible for this Xrn1
repression in Hepatitis C virus and Bovine Viral Diarrhea virus. These observations serve as the foundation for
this proposal to gain in-depth mechanistic insights into molecular mechanisms of Xrn1 repression and
regulation that are disrupted by flavivirus RNAs. In Aim 1, we will identify the sequence/structural requirements
of IRES-mediated Xrn1 repression and determine whether this is a common property of other viral IRES
elements. The goal of Aim 2 is understand at a mechanistic level why the repression of Xrn1 by flavivirus
RNAs results in the apparent shut down of the entire 5'-3' mRNA decay pathway – not just the exonucleolytic
digestion step. Uncovering the interplay and feedback regulation of the decay factors in the 5'-3' RNA decay
pathway will provide novel insights into how the cell normally regulates this decay pathway and integrate it into
the overall process of gene expression. In the third aim we will expand our studies on Xrn1 stalling and
investigate whether it is an approach used by the cell to remodel cellular transcripts. In the final Aim, we will
characterize key biological aspects of Xrn1 repression from the perspective of both the cell and the virus. A
key focus of this part will be on the dysregulation of cellular mRNA stability by flaviviruses that results in
dramatic changes in cellular gene expression that could play a significant role in HCV-mediated oncogenesis.
黄病毒科(Flaviviridae)是一个正义RNA病毒家族,其包含许多重要的人类基因组。
病原体这些RNA病毒引起细胞病理学的许多分子机制
疾病没有明确描述。细胞mRNA衰变机制,特别是5 '-3'途径
由核糖核酸外切酶Xrn 1介导,在调节基因的丰度和质量方面起着重要作用
细胞中的表达。黄病毒与宿主相互作用的研究不足,但仍然非常重要,
包括病毒RNA如何被细胞mRNA衰变机制保护而不被降解,
病毒RNA稳定化策略对细胞mRNA稳定性调节的影响。我们有
最近观察到,黄病毒通过使用独特的捕获酶来抑制Xrn 1的活性,
病毒RNA的结构化区域。有趣的是,正是5' UTR IRES区域负责这个Xrn 1
抑制丙型肝炎病毒和牛病毒性腹泻病毒。这些观察结果是
这一提议旨在深入了解Xrn 1抑制的分子机制,
调节被黄病毒RNA破坏。在目标1中,我们将确定序列/结构要求
IRES介导的Xrn 1抑制,并确定这是否是其他病毒IRES的共同特性
元素目的2的目标是在机制水平上理解为什么黄病毒抑制Xrn 1
RNA导致整个5 '-3' mRNA衰变途径的明显关闭-而不仅仅是核酸外切酶,
消化步骤。揭示5 '-3' RNA衰变中衰变因子的相互作用和反馈调节
这将为细胞如何正常调节这种衰变途径并将其整合到细胞中提供新的见解。
基因表达的整个过程。在第三个目标中,我们将扩展我们对Xrn 1失速的研究,
研究它是否是细胞用来重塑细胞转录本的一种方法。在最后的目标中,我们将
从细胞和病毒的角度描述Xrn 1抑制的关键生物学方面。一
本部分的重点是黄病毒引起的细胞mRNA稳定性失调,
细胞基因表达的显著变化可能在HCV介导的肿瘤发生中起重要作用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Jeffrey Wilusz其他文献
Jeffrey Wilusz的其他文献
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{{ truncateString('Jeffrey Wilusz', 18)}}的其他基金
Pathological Implications of Repression of Cellular RNA Decay by Zika Virus
寨卡病毒抑制细胞 RNA 衰变的病理学意义
- 批准号:
9298165 - 财政年份:2017
- 资助金额:
$ 37.27万 - 项目类别:
Flavivirus non-coding RNAs and the Host mRNA Decay Machinery
黄病毒非编码 RNA 和宿主 mRNA 衰变机制
- 批准号:
9356456 - 财政年份:2016
- 资助金额:
$ 37.27万 - 项目类别:
Flavivirus non-coding RNAs and the Host mRNA Decay Machinery
黄病毒非编码 RNA 和宿主 mRNA 衰变机制
- 批准号:
9238132 - 财政年份:2016
- 资助金额:
$ 37.27万 - 项目类别:
A novel antiviral approach using the cellular RNA decay machinery
一种利用细胞 RNA 衰变机制的新型抗病毒方法
- 批准号:
8261431 - 财政年份:2011
- 资助金额:
$ 37.27万 - 项目类别:
A novel antiviral approach using the cellular RNA decay machinery
一种利用细胞 RNA 衰变机制的新型抗病毒方法
- 批准号:
7675653 - 财政年份:2009
- 资助金额:
$ 37.27万 - 项目类别:
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