Defining how the DNA- and RNA-binding protein SFPQ represses Epstein-Barr Virus lytic reactivation
定义 DNA 和 RNA 结合蛋白 SFPQ 如何抑制 Epstein-Barr 病毒裂解再激活
基本信息
- 批准号:10537257
- 负责人:
- 金额:$ 6.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-11-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAdultArchitectureB-LymphocytesBindingBiologyBiopsyBurkitt LymphomaCRISPR screenCarcinomaCell CompartmentationCellsDNADNA BindingDNA-Binding ProteinsDetectionDevelopmentDiseaseDown-RegulationEBV-associated diseaseEnvironmentEpithelialEpithelial CellsEpstein-Barr Virus InfectionsEpstein-Barr Virus latencyEpstein-Barr pathogenesisEquilibriumFoundationsGene ExpressionGenetic TranscriptionGenomeGenomic SegmentGenomicsGlutamineGoalsHIVHistonesHodgkin DiseaseHospitalsHumanHuman Herpesvirus 4ImmuneImmune EvasionInfectious MononucleosisIntegration Host FactorsKnock-outKnowledgeLeadLifeLocationLymphomaLyticLytic PhaseLytic VirusMalignant NeoplasmsMalignant neoplasm of nasopharynxMediatingMemory B-LymphocyteMethodsMicroscopyMolecular ConformationMolecular VirologyNasopharynx CarcinomaNuclearNuclear ProteinOralOropharyngealPopulationProlineProtein SplicingProteinsRNARNA BindingRNA SplicingRNA-Binding ProteinsRepressionResearchResourcesRoleRunningSalivaSalivarySiteStomach CarcinomaStructureTestingTherapeuticTissuesTonsilTonsillar TissueTrainingTranscriptional RegulationUntranslated RNAViral GenesViral GenomeVirus DiseasesVirus LatencyWomanWorkcollaborative environmentcraniofacialgammaherpesvirusinsightinterdisciplinary approachlive cell imaginglytic gene expressionlytic replicationmedical schoolsnervous system disordernovel therapeutic interventionoral cavity epitheliumpathogenpathogenic viruspost-transplantprogramspromoterreactivation from latencyscientific atmospheretranscription factortranscriptomicstransmission processviral genomicsvirus host interaction
项目摘要
PROJECT SUMMARY/ABSTRACT
Epstein-Barr virus (EBV) is spread through saliva, infects oropharyngeal tissues including the tonsillar epithelium,
and establishes life-long latency in the B-cell compartment in over 95% of the global adult human population.
The oral transmission of EBV can result in infectious mononucleosis and can lead to several B-cell and epithelial
cancers, including Burkitt lymphoma. This frequently presents as craniofacial and nasopharyngeal carcinomas.
EBV uses both latent and lytic phases of its replication cycle to colonize the oropharynx and tonsils. Reactivation
from latency is closely tied to EBV pathogenicity; however, the mechanisms that maintain latency and regulate
reactivation in tonsillar memory B-cells and in EBV-associated diseases remain incompletely understood.
Because EBV can evade immune detection while latent, most currently available therapies cannot harness the
presence of the latent EBV genome. Developing a detailed understanding of the switch from latency to lytic
reactivation may lay the foundation for lytic induction therapeutic strategies. One of the challenges to
understanding the EBV lytic switch is to define the host factors necessary for maintaining EBV latency and how
these factors are circumvented by EBV to allow reactivation. To begin to address this question, a human
CRISPR/Cas9 screen was performed in Burkitt B-cells that were originally derived from a craniofacial biopsy. It
showed that knockout of the human nuclear protein splicing factor proline and glutamine rich (SFPQ) strongly
induces EBV lytic reactivation. SFPQ binds both DNA and RNA and is known to regulate both transcription and
RNA splicing. Thus, SFPQ is poised as a master regulator of human and viral gene expression and viral genomic
conformation during EBV latency. The goal of this study is to test the hypothesis that SFPQ suppresses
EBV lytic reactivation in both DNA- and RNA- dependent manners and that EBV relieves this suppression
by redistributing SFPQ to paraspeckles. Aim 1 is to determine the mechanism by which SFPQ represses EBV
lytic reactivation. Aim 2 is to define the factors that mediate SFPQ subnuclear redistribution and function upon
lytic reactivation. Molecular virology, transcriptomic, genomic, and microscopy approaches will be integrated to
test this hypothesis. Understanding how SFPQ regulates the EBV and host genomes during latency and how
SFPQ responds during lytic reactivation will contribute to a fundamental knowledge gap in how EBV subverts
host factors to colonize oropharyngeal tissues and the B-cell compartment. This study may lay the foundation
for lytic induction therapeutic strategies. The Brigham and Women’s Hospital at Harvard Medical School will
provide an environment rich in both physical and intellectual resources for completion of this training.
Furthermore, working with Dr. Gewurz in the collaborative atmosphere of his lab will enhance training in multi-
disciplinary approaches to study EBV-host interactions. Altogether, this is an excellent environment for scientific
training for development towards running an independent research program.
项目总结/文摘
项目成果
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