dsRNA production and sensing during DNA virus infection
DNA病毒感染过程中dsRNA的产生和传感
基本信息
- 批准号:10893810
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-03 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAdenovirus InfectionsAdenovirusesAdvisory CommitteesAntibodiesAntisense RNAAntiviral ResponseApoptosisBase PairingBindingBinding ProteinsBioinformaticsBiologyCell NucleusCellsCellular StressClustered Regularly Interspaced Short Palindromic RepeatsComplexCoupledCytoplasmDNADNA Virus InfectionsDNA VirusesDNA biosynthesisDataDouble Stranded DNA VirusDouble-Stranded RNAEnvironmentExhibitsFacultyFluorescent in Situ HybridizationFractionationGene ExpressionGene Expression RegulationGenetic TranscriptionGoalsHerpesviridaeHuman Herpesvirus 4Immune responseImmunoprecipitationIn Situ HybridizationInfectionInnate Immune ResponseInnate Immune SystemIntegration Host FactorsInterferonsK-Series Research Career ProgramsKnowledgeLearning SkillLigaseLocationMass Spectrum AnalysisMediatingMentorsMessenger RNAModelingModernizationModificationMolecularMutateNuclearOutcomeOutcome StudyPRKR genePathway interactionsPatternPennsylvaniaPhasePlayPositioning AttributeProcessProductionPropertyProtein BiosynthesisRNARNA BindingRNA ProcessingRNA SplicingRNA VirusesRegulationRegulator GenesResearchResearch PersonnelResolutionRibonucleasesRoleScientistSeminalSignal TransductionSimplexvirusStructureSystemTechniquesTechnologyTestingTrainingTranscriptUniversitiesViralViral GenesViral GenomeViral ProteinsVirusVirus DiseasesVirus ReplicationWorkantagonistcareerds RNA-Binding Proteinsds-DNAdsRNA adenosine deaminaseendonucleaseexperienceexperimental studyimprovedinhibitorinsightmutantnext generation sequencingnoveloligoadenylatepathogenprotein expressionreceptorresponsesensorskillssuccesstooltranscriptometranscriptome sequencingviral detectionvirus host interaction
项目摘要
Project Summary
Viral infections are known to produce double-stranded RNA (dsRNA), a molecule that is not present at
high levels in uninfected host cells. This property of dsRNA is exploited by cells to sense viral infection and
deploy anti-viral countermeasures. While DNA viruses produce viral mRNA molecules that look identical to
cellular RNA, many DNA viruses are thought to produce dsRNA due to the process of symmetrical gene
transcription of both strands of DNA. When we looked for the presence of dsRNA during adenovirus (AdV)
infection using modern antibody-based techniques we found no evidence of dsRNA production, directly
countering the existing dogma. Considering many DNA viruses encode antagonists of cellular dsRNA-sensing
pathways, this directly calls into question the relevance of dsRNA sensing during DNA virus infection. While
wildtype AdV did not produce detectable dsRNA, viral mutants which can no longer splice their own transcripts
efficiently saw robust accumulation of dsRNA within the nucleus. Furthermore, these dsRNA-producing mutants
activated cytoplasmic sensors of dsRNA such as PKR and RNaseL. The use of mutant viruses provides a unique
opportunity to assess host responses to dsRNAs derived from DNA virus infection. Still, the question of how
these nuclear dsRNAs are detected by cytoplasmic sensors remains unanswered.
By completion of this mentored career development award I will gain training in RNA sequencing,
quantitative mass spectrometry, and the bioinformatics approaches to analyze both. In the mentored phase I will
continue my training with AdV, a relatively simple virus that provides powerful tools to understand regulation and
sensing of DNA virus derived nuclear dsRNA. In the independent phase I will utilize herpes simplex virus (HSV-
1), a complex virus able to exert control over dsRNA-sensing pathways, as a model virus to study exploitation of
dsRNA for viral gene regulation. This proposal will reveal the binding partners and localizations of DNA virus
derived dsRNA as well as new strategies in which viruses exploit host cell gene regulatory machinery. In Aim 1
I will determine the localization and binding partners of viral dsRNA using immunoprecipitation coupled to next
generation sequencing and mass spectrometry. These experiments will determine how nuclear dsRNA leads to
activation of cytoplasmic sensors, as well as how AdV interacts with and blocks these novel pathways. In Aim 2
I will determine how HSV-1 regulates its own viral gene expression using the nuclear retention of overlapping
viral transcript pairs that form dsRNA. The outcome of these experiments will reveal a new mechanism for viral
gene regulation with broad implications for all herpesviruses. The outstanding training environment at CHOP
and the University of Pennsylvania, coupled with the excellent advisory committee I have assembled, will greatly
facilitate my research during the mentored phase as well as launch my career with the skills necessary to
transition to an independent faculty position studying how host cells sense the RNAs generated by DNA viruses.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alexander Matthew Price其他文献
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{{ truncateString('Alexander Matthew Price', 18)}}的其他基金
dsRNA production and sensing during DNA virus infection
DNA病毒感染过程中dsRNA的产生和传感
- 批准号:
10460518 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
dsRNA production and sensing during DNA virus infection
DNA病毒感染过程中dsRNA的产生和传感
- 批准号:
10190333 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
Temporal regulation of the essential Epstein-Barr virus oncoprotein LMP1
EB 病毒必需癌蛋白 LMP1 的时间调控
- 批准号:
8594953 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
Temporal regulation of the essential Epstein-Barr virus oncoprotein LMP1
EB 病毒必需癌蛋白 LMP1 的时间调控
- 批准号:
8727986 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
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