ADAR1-mediated antiviral response in Zika virus (ZIKV) infection
ADAR1 介导的寨卡病毒 (ZIKV) 感染抗病毒反应
基本信息
- 批准号:10373627
- 负责人:
- 金额:$ 23.1万
- 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:2022-05-13 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAdenosineAdenovirus VectorAdultAffectAmino Acid SequenceAntiviral ResponseAntiviral TherapyAtrophicAttenuatedAutoimmune DiseasesBindingBinding ProteinsBlood VesselsBlood-Retinal BarrierCellsClinicalCodeCre lox recombination systemDRADA2b proteinDataDouble-Stranded RNAEndothelial CellsEndotheliumEnzymesEventEyeEye diseasesFlavivirusFunctional disorderGene DeliveryGene Expression RegulationGenesGenetic TranscriptionGoalsGuanosineHistologyHumanImmune responseInfantInfectionInflammationInflammatoryInflammatory ResponseInnate Immune ResponseInosineInterferonsKnowledgeLaboratoriesLeadLentivirusLongitudinal StudiesMalignant NeoplasmsMediatingMessenger RNAModalityMusNatural ImmunityOcular PathologyPathogenesisPathologicPathologyPatternPlasmidsPlayPost-Transcriptional RegulationProductionPropertyProteinsProteomePublic HealthRNARNA EditingRNA IRNA SplicingRNA VirusesRNA-specific adenosine deaminase 3Replication-Associated ProcessReportingRetinaRoleSignal TransductionSiteStructure of retinal pigment epitheliumTestingTranscriptTranslationsVaccinesViralViral GenomeViral load measurementVirus DiseasesVirus ReplicationVisual impairmentZIKV infectionZika Virusadenosine deaminasebasecytokinedsRNA adenosine deaminaseeconomic implicationfundus imaginggenome analysisgenome-widehuman pathogenimmune activationin vivoknock-downmRNA Precursormouse modelmutantneonatal micenovel therapeuticsoverexpressionpathogenpreventrational designresponsesocial implicationtherapeutic targettranscriptometranscriptome sequencingtranscriptomicsviral RNAwhole genome
项目摘要
Project Summary
In response to viral infections, host cells trigger an innate/anti-viral immune response,
predominantly by producing the interferons (IFNs) and IFN-stimulated genes (ISGs). These anti-
viral responses promote inflammation, immune cell activation, and viral clearance. We recently
reported that retinal pigment epithelium (RPE) and retinal vascular or choroidal endothelium are
highly permissive to Zika virus (ZIKV) infection and elicit antiviral response with increased
production of IFNs and ISGs. The transcriptomic analysis of ZIKV-infected RPE revealed the
induction of adenosine deaminases acting on RNA1 (ADAR1), a potent ISG, which can exert pro-
or antiviral activity by A-to-I editing of the host and viral RNA. The role and mechanisms of action
of ADAR1 during ZIKV and related flaviviruses have not been studied till now. Our preliminary
studies show that 1) ADAR1 is up-regulated at the transcript, as well as, protein levels upon ZIKV
infection in RPE cells, and 2) ADAR1 overexpression reduced, while ADAR1 knockdown
increased, ZIKV replication in RPE cells. These findings led us to investigate the role of ADAR1
in retinal innate immunity to ZIKV and other flaviviruses. Thus, the overall goal of this proposal is
to determine the mechanisms of antiviral actions of ADAR1 in attenuating ZIKV replication in RPE
cells (Aim 1); and to determine the consequences of ADAR1 ablation and ADAR1 overexpression
on ZIKV-induced chorioretinal atrophy in a mouse model (Aim 2). The proposed studies will
broaden and deepen our knowledge of the antiviral response during ocular ZIKV infection. Our
studies could also identify new targets and treatment modalities based on the RNA editing ability
of the host.
项目摘要
响应于病毒感染,宿主细胞触发先天/抗病毒免疫应答,
主要通过产生干扰素(IFN)和IFN刺激基因(ISG)。这些反-
病毒应答促进炎症、免疫细胞活化和病毒清除。我们最近
据报道,视网膜色素上皮(RPE)和视网膜血管或脉络膜内皮是
高度允许寨卡病毒(ZIKV)感染,并引发抗病毒反应,
生产IFN和ISG。ZIKV感染的RPE的转录组学分析显示,
诱导腺苷脱氨酶作用于RNA 1(ADAR 1),一种有效的ISG,可以发挥促增殖作用,
或通过宿主和病毒RNA的A-to-I编辑的抗病毒活性。作用和作用机制
ZIKV和相关黄病毒中ADAR 1的表达至今尚未研究。我们的初步
研究表明,1)ADAR 1在ZIKV后在转录物以及蛋白质水平上上调,
感染RPE细胞,2)ADAR 1过表达减少,而ADAR 1敲低
RPE细胞中ZIKV复制增加。这些发现促使我们研究ADAR 1在
在视网膜先天免疫ZIKV和其他黄病毒。因此,本提案的总体目标是
确定ADAR 1在减弱RPE中ZIKV复制中的抗病毒作用机制
细胞(目的1);并确定ADAR 1消融和ADAR 1过表达的后果
对小鼠模型中ZIKV诱导的脉络膜视网膜萎缩的影响(目的2)。拟议的研究将
扩大和加深我们对眼部ZIKV感染期间抗病毒反应的认识。我们
研究还可以根据RNA编辑能力确定新的靶点和治疗方式,
的主机。
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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Ashok Kumar其他文献
Ashok Kumar的其他文献
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{{ truncateString('Ashok Kumar', 18)}}的其他基金
ADAR1-mediated antiviral response in Zika virus (ZIKV) infection
ADAR1 介导的寨卡病毒 (ZIKV) 感染抗病毒反应
- 批准号:
10621913 - 财政年份:2022
- 资助金额:
$ 23.1万 - 项目类别:
Age-associated impaired executive function: Rescue by NMDA receptor upregulation
与年龄相关的执行功能受损:通过 NMDA 受体上调来挽救
- 批准号:
10033493 - 财政年份:2020
- 资助金额:
$ 23.1万 - 项目类别:
Role of ABCG1 in Zika virus induced chorioretinal atrophy
ABCG1 在寨卡病毒诱导的脉络膜视网膜萎缩中的作用
- 批准号:
9436896 - 财政年份:2018
- 资助金额:
$ 23.1万 - 项目类别:
Role of AMP-activated protein kinase in bacterial endophthalmitis - Diversity Supplement
AMP 激活蛋白激酶在细菌性眼内炎中的作用 - Diversity Supplement
- 批准号:
10206590 - 财政年份:2017
- 资助金额:
$ 23.1万 - 项目类别:
Role of AMP-activated protein kinase in bacterial endophthalmitis
AMP 激活蛋白激酶在细菌性眼内炎中的作用
- 批准号:
9899998 - 财政年份:2017
- 资助金额:
$ 23.1万 - 项目类别:
Targeting NAD metabolism to ameliorate bacterial endophthalmitis
靶向 NAD 代谢改善细菌性眼内炎
- 批准号:
10445516 - 财政年份:2017
- 资助金额:
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Mechanisms of Inflammation Resolution in Bacterial Endophthalmitis
细菌性眼内炎的炎症消退机制
- 批准号:
10231125 - 财政年份:2017
- 资助金额:
$ 23.1万 - 项目类别:
Mechanisms of Inflammation Resolution in Bacterial Endophthalmitis
细菌性眼内炎的炎症消退机制
- 批准号:
10002232 - 财政年份:2017
- 资助金额:
$ 23.1万 - 项目类别:
Targeting NAD metabolism to ameliorate bacterial endophthalmitis
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- 批准号:
10621770 - 财政年份:2017
- 资助金额:
$ 23.1万 - 项目类别:
Toll-like receptors and bacterial endophthalmitis
Toll样受体与细菌性眼内炎
- 批准号:
8387011 - 财政年份:2010
- 资助金额:
$ 23.1万 - 项目类别:
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