Characterizing Vpr-mediated Activation of the DNA Damage Response (DDR) in HIV Replication
HIV 复制中 Vpr 介导的 DNA 损伤反应 (DDR) 激活的特征
基本信息
- 批准号:10613920
- 负责人:
- 金额:--
- 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:2022-07-01 至 2023-07-02
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeBIRC3 geneBiological AssayBiologyCell Cycle ArrestCellsCollaborationsComet AssayComplexConsequences of HIVDNA DamageDNA Replication DamageDNA VirusesDataDendritic CellsDevelopmentGenesGenetic TranscriptionGenomeGoalsHIVHIV InfectionsHIV-1HIV-2IL8 geneImmuneImmunofluorescence ImmunologicInfectionKnock-outKnowledgeLentivirusLettersLife Cycle StagesLinkM cellMacrophageMediatingMolecularMolecular BiologyMutation AnalysisNBS1 geneNF-kappa BNatural ImmunityNuclearPathway interactionsPersonsPhenotypePrimate LentivirusesQuantitative Reverse Transcriptase PCRRNA VirusesRepressionResearchRoleScientistSignal PathwaySignal TransductionTestingUp-RegulationViralVirusVirus ReplicationVirus-like particleantiretroviral therapyassaultgenotoxicityglobal healthimprovedin vivoinhibitorinsightknock-downlive cell imagingmonocytenovelp53-binding protein 1p65recruitresponsesuccesstranscriptome sequencingtumorigenesisvpr Gene Products
项目摘要
PROJECT SUMMARY
HIV continues to be a major burden to global health as it accounts for approximately 36.9 million people living
with acquired immunodeficiency syndrome (AIDS). Scientists have made considerable strides in understanding
the basic molecular biology of HIV, which directly led to the development of effective antiretroviral therapy (ART).
Yet, despite years of research, we currently do not have a complete picture of the HIV lifecycle to help develop
a functional cure. By understanding key steps in the HIV lifecycle and establishing the cellular consequences of
HIV infection, we can develop novel treatments and a functional cure, which take advantage of the cellular
markers that HIV infection leaves behind. One key aspect of HIV biology that remains unclear is Vpr, an
accessory gene without a known primary conserved function. Vpr is evolutionarily conserved among extant
primate lentiviruses and is required for virus replication in vivo. Although Vpr enhances viral replication in
monocyte-derived macrophages and monocyte-derived dendritic cells, it remains unclear how Vpr enhances
replication. An emerging phenotype described for Vpr is engagement with the DNA damage response (DDR).
The DDR is a signaling cascade responsible for safeguarding the genome from genotoxic assault that is well
understood. Modulation of the DDR is often seen by diverse RNA and DNA viruses to promote tumorigenesis or
enhancement of viral replication. Most interestingly, we found that Vpr can induce DNA damage and the ability
of Vpr to induce DNA damage is conserved among HIV-1 and HIV-2. In addition, activation of the DDR is linked
to NF-kB and innate immunity. Our preliminary data suggest that Vpr-induced DNA damage activates NF-kB.
This data contributes to our central hypothesis that Vpr-induced DNA damage signals through the classical
DDR to activate NF-kB target genes and enhance viral replication.
In this proposal, we will investigate how and why Vpr induces DNA damage. In Aim 1, I will characterize the
requirements and downstream signaling of Vpr-induced DNA damage. Completing this aim will shed light on
how Vpr induces DNA damage and establishes if the classical DDR is activated or if non-classical activation
mechanisms await to be explored. In Aim 2, I will identify the role of Vpr-induced DNA damage activation of NF-
κB target genes in HIV replication. Completing this aim will determine why Vpr causes DNA damage and will
establish the molecular mechanism for Vpr-enhancement of viral replication. Overall, we will gain insight into
how HIV infected cells are dealing with DNA damage. The long-term goal is to leverage our understanding of
DNA damage in HIV infected cells to develop improved treatments and a functional cure for people with
HIV/AIDS.
项目摘要
艾滋病毒仍然是全球卫生的一个主要负担,约有3690万人感染艾滋病毒。
获得性免疫缺陷综合症(艾滋病)。科学家在理解方面取得了长足的进步
艾滋病毒的基本分子生物学,这直接导致了有效的抗逆转录病毒疗法(ART)的发展。
然而,尽管经过多年的研究,我们目前还没有完整的艾滋病毒生命周期来帮助开发
功能性治疗通过了解艾滋病毒生命周期中的关键步骤,并确定
艾滋病毒感染后,我们可以开发新型治疗方法和功能性治疗方法,利用细胞的作用
艾滋病毒感染后留下的标记。艾滋病毒生物学的一个关键方面仍然不清楚,那就是Vpr,一种
辅助基因没有已知的主要保守功能。Vpr在现存的物种中是进化保守的
灵长类慢病毒,并且是体内病毒复制所必需的。虽然Vpr在体内增强病毒复制,
单核细胞衍生的巨噬细胞和单核细胞衍生的树突状细胞,目前尚不清楚Vpr如何增强
复制的Vpr描述的一种新出现的表型是与DNA损伤反应(DDR)接合。
DDR是一个信号级联,负责保护基因组免受基因毒性攻击,
明白DDR的调节通常由不同的RNA和DNA病毒看到,以促进肿瘤发生或转移。
增强病毒复制。最有趣的是,我们发现Vpr可以诱导DNA损伤,
Vpr诱导DNA损伤的作用在HIV-1和HIV-2中是保守的。此外,复员方案的启动与
NF-kB和先天免疫。我们的初步数据表明,Vpr诱导的DNA损伤激活NF-κ B。
这些数据有助于我们的中心假设,即Vpr诱导的DNA损伤信号通过经典的
DDR激活NF-κ B靶基因并增强病毒复制。
在这个提议中,我们将研究Vpr如何以及为什么诱导DNA损伤。在目标1中,我将描述
Vpr诱导的DNA损伤的下游信号传导。完成这一目标将有助于
Vpr如何诱导DNA损伤并确定经典DDR是否被激活或非经典激活
机制有待探索。在目的2中,我将确定Vpr诱导的DNA损伤激活NF-κ B的作用。
HIV复制中的κB靶基因。完成这一目标将确定为什么Vpr会导致DNA损伤,
建立Vpr增强病毒复制的分子机制。总的来说,我们将深入了解
HIV感染细胞如何处理DNA损伤长期目标是利用我们对
HIV感染细胞中的DNA损伤,以开发改进的治疗方法和功能性治疗方法,
艾滋病毒/艾滋病的
项目成果
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Carina Sandoval其他文献
Carina Sandoval的其他文献
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{{ truncateString('Carina Sandoval', 18)}}的其他基金
Characterizing Vpr-mediated Activation of the DNA Damage Response (DDR) in HIV Replication
HIV 复制中 Vpr 介导的 DNA 损伤反应 (DDR) 激活的特征
- 批准号:
10483976 - 财政年份:2022
- 资助金额:
-- - 项目类别: