Mammalian Reovirus Post-transcriptional Gene Regulation
哺乳动物呼肠孤病毒转录后基因调控
基本信息
- 批准号:7754769
- 负责人:
- 金额:$ 3.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-01 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:ADAR1AdenosineAutomobile DrivingBiological ModelsBiologyCellsComplexConserved SequenceDNADevelopmentDiagnosisDiagnosticDiseaseDouble-Stranded RNAEctopic ExpressionElementsEmbryoEngineeringEnzymesFellowshipFibroblastsFirefly LuciferasesFosteringFunctional RNAGene ExpressionGene Expression RegulationGenomeGoalsHealthImaging technologyImmune responseIn VitroIndiumInfectionInosineL CellsLeadLife Cycle StagesLuciferasesMediatingMetabolicModalityMolecular BiologyMusMutationNervous system structureNeuraxisNeuronsNucleic Acid Regulatory SequencesOpen Reading FramesPathogenesisPlasmidsPost-Transcriptional RegulationPreventionProcessProtein BiosynthesisProtein IsoformsProteinsProteomicsRNARNA EditingRNA InterferenceRNA StabilityRNA VirusesRNA-Binding ProteinsRattusRegulationRegulatory ElementReoviridae InfectionsReovirusReporterResearchRibonucleoproteinsRodentRoleStructure-Activity RelationshipSystemTherapeuticTissuesTranscriptTranslational RegulationTranslationsViralViral GenesViral GenomeViral ProteinsVirusVirus DiseasesVirus ReplicationVirus-Cell Membrane InteractionWorkbasecell growth regulationcell injurycell transformationcell typecellular imagingcis acting elementdsRNA adenosine deaminasegain of functiongenetic regulatory proteinin vivoinjuredinsightintermolecular interactionmutantneurotropicnovel strategiespositional cloningprogramsresearch studyviral RNAvirus host interaction
项目摘要
DESCRIPTION (provided by applicant): The overarching goal of this fellowship application is to provide support for work which will focus on dissecting the structure-function relationships in ribonucleoprotein (RNP) complexes that mediate post-transcriptional gene regulation in viruses with double-strandedA (dsRNA) genomes. Mammalian reoviruses, an established model system of dsRNA virus replication, will be used for these studies. The central hypothesis is that the mechanism of reovirus RNA regulation involves specific cis-acting elements in viral RNA with cellular and viral RNA binding proteins. Two specific aims are proposed to obtain mechanistic insight into post-transcriptional control of reovirus RNA. In Specific Aim 1, the role of the RNA-editing enzyme, ADAR1, in the reovirus infectious cycle will be determined using ADAR1-deficient transformed cells, murine embryonic fibroblasts and primary cultures of explanted rat neurons. Experiments will be performed to determine whether viral RNAs serve as editing substrates and to assess the effect of reovirus infection on editing cellular RNAs. In Specific Aim 2, viral RNA translational regulatory elements will be defined using chimeric reporter RNAs containing the luciferase open reading frame fused to conserved sequences from the 5' and 3' terminal regions of viral RNAs. The activity of reporter RNAs will be studied using cell-free translation systems, transformed cells, and primary neuronal cultures. Viruses containing mutations in translational control elements will be rescued by plasmid-based reverse genetics, and effects of these changes on viral protein synthesis and replication will be determined by infecting transformed cells, murine embryonic fibroblasts, and explanted neurons. Health relevance- the work proposed in this application has great potential to advance our understanding of virus-cell interactions that promote cell injury and disease in the host. The ability to conduct research about the molecular biology of viruses will lead to a better understanding of pathogenesis and immune responses to viral infection. This work will also foster the development of viral preventative, diagnostic, and therapeutic modalities against pathogenic RNA viruses.
描述(由申请人提供):该奖学金申请的总体目标是为重点剖析核糖核蛋白(RNP)复合物的结构-功能关系的工作提供支持,该复合物介导双链A病毒中的转录后基因调控( dsRNA)基因组。哺乳动物呼肠孤病毒是一种已建立的 dsRNA 病毒复制模型系统,将用于这些研究。核心假设是呼肠孤病毒RNA调节机制涉及病毒RNA中的特定顺式作用元件以及细胞和病毒RNA结合蛋白。为了深入了解呼肠孤病毒 RNA 转录后控制的机制,提出了两个具体目标。在具体目标 1 中,将使用 ADAR1 缺陷型转化细胞、鼠胚胎成纤维细胞和外植大鼠神经元的原代培养物来确定 RNA 编辑酶 ADAR1 在呼肠孤病毒感染周期中的作用。将进行实验以确定病毒 RNA 是否充当编辑底物,并评估呼肠孤病毒感染对编辑细胞 RNA 的影响。在具体目标 2 中,将使用含有与病毒 RNA 5' 和 3' 末端区域的保守序列融合的荧光素酶开放阅读框的嵌合报告 RNA 来定义病毒 RNA 翻译调控元件。将使用无细胞翻译系统、转化细胞和原代神经元培养物来研究报告RNA的活性。含有翻译控制元件突变的病毒将通过基于质粒的反向遗传学来拯救,并且这些变化对病毒蛋白质合成和复制的影响将通过感染转化细胞、鼠胚胎成纤维细胞和外植神经元来确定。健康相关性——本申请中提出的工作具有巨大的潜力,可以促进我们对促进宿主细胞损伤和疾病的病毒-细胞相互作用的理解。进行病毒分子生物学研究的能力将有助于更好地了解病毒感染的发病机制和免疫反应。这项工作还将促进针对致病性 RNA 病毒的病毒预防、诊断和治疗方式的发展。
项目成果
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