Mechanism and Therapeutic Implication of Host Cell Telomerase Modulation by Human Cytomegalovirus
人巨细胞病毒调节宿主细胞端粒酶的机制和治疗意义
基本信息
- 批准号:10388560
- 负责人:
- 金额:$ 5.18万
- 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:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAgingAntiviral AgentsAntiviral TherapyAttenuatedBindingBiological AssayBiologyCell LineCell SurvivalCellsChromosomesChronicClinicalClinical ManagementCongenital AbnormalityCytomegalovirusDNADNA Microarray ChipDataDevelopmentDiseaseDoseEctopic ExpressionEnzymesFutureGanciclovirGenesGoalsHerpesviridaeHumanHyperactivityImmunocompetenceImmunocompetentImmunocompromised HostImpairmentIndividualInfectionLaboratoriesLatent virus infection phaseLeadLifeLife Cycle StagesLightLinkMalignant NeoplasmsMass Spectrum AnalysisMeasuresMediatingMedicalMethodsMolecularMononuclearMorbidity - disease rateOncogenicPathogenicityPathway interactionsPharmacologic SubstancePlayPopulationProductionProteinsRNA-Directed DNA PolymeraseRecrudescencesRepressionRiskRoleSeroprevalencesSmall Interfering RNAStressSystemTelomeraseTelomerase InhibitorTelomerase inhibitionTestingTetanus Helper PeptideTherapeuticTranscriptUp-RegulationVaccinesViralViral GenesViral ProteinsVirusVirus ReplicationWorkattenuationbaseburden of illnesscell typechromatin immunoprecipitationclinically relevantclinically significantcongenital infectionds-DNAeffective therapyexperimental studygene productgenetic inhibitorglobal healthimprovedin uteroinhibitorinsightknock-downneonatal infectionnovel therapeuticspromoterresponsesmall hairpin RNAtelomereviral RNAviral resistance
项目摘要
Project Summary
Human Cytomegalovirus (HCMV) is a herpesvirus whose seroprevalence and disease burden remain high
worldwide. While disease is often mild in immunocompetent individuals, it is often severe for
immunocompromised individuals, and congenital infection remains a leading cause of birth defects. There is
currently no vaccine or permanent effective anti-viral therapy against HCMV. The host enzyme telomerase,
which maintains telomeres to protect the integrity of DNA, is key for cell survival and has been implicated in
several diseases including cancer. Telomerase has been implicated as an important agent in the life cycles
and potential oncogenic activity of several herpesviruses, and recently has been shown to be hyperactive in
response to active HCMV infection. Furthermore, telomerase inhibition has been associated with a significant
reduction of viral infectivity in laboratory and clinical strains of HCMV. However, the significance of telomerase
in the HCMV viral life cycle, and the potential therapeutic implications of this relationship, remain unexplored.
We hypothesize host telomerase is important for the HCMV viral life cycle. We will first establish telomerase
activity upregulation upon HCMV infection, and reduced HCMV replication following telomerase inhibition, in
multiple strains and cell lines using several approaches to telomerase repression. Assays of telomerase
activity in the presence of pharmaceutical telomerase inhibitors BIBR1532 and MST-312 will establish a
reduction of viral infectivity following telomerase inhibition in both laboratory and clinical strains. Subsequent
assays using inducible genetic inhibitors, specifically siRNA and inducible shRNA constructs against hTERT,
will test whether reduction of viral replication is a result of telomerase inhibition and not off-target effects. To
define the mechanism of action by which HCMV upregulates telomerase activity, we will assess telomerase
activity following ectopic expression and shRNA-mediated knockdown of key viral genes, and implicated gene
products will be subjected to binding assays in infected and telomerase-inhibited infected conditions to assess
association with DNA via ChiP and QTIP assays, and with other proteins via IP and mass spectrometry. ChiP
assays in infected and telomerase-inhibited infected conditions will also be performed on host proteins
previously shown to influence telomerase activity. To define the function of telomerase in the viral life cycle, we
will conduct differentially-timed inhibition of telomerase and assess the viral gene class(es) the activity of which
is constrained by the absence of telomerase. Overall, these experiments will establish the potential clinical
relevance of telomerase in HCMV infection and define both the mechanism of action by which HCMV
upregulates telomerase activity and the function of telomerase in the viral life cycle. Increased understanding
of these relationships may provide insight into other herpesviruses, inform clinical HCMV management, and
lead to new anti-viral therapies.
项目概要
人类巨细胞病毒 (HCMV) 是一种疱疹病毒,其血清流行率和疾病负担仍然很高
全世界。虽然对于免疫功能正常的个体来说,疾病通常是轻微的,但对于免疫功能正常的个体来说,疾病通常是严重的
免疫功能低下的个体和先天性感染仍然是出生缺陷的主要原因。有
目前尚无针对 HCMV 的疫苗或永久有效的抗病毒疗法。宿主酶端粒酶,
它维持端粒以保护 DNA 的完整性,是细胞生存的关键,并与
包括癌症在内的多种疾病。端粒酶被认为是生命周期中的重要媒介
和几种疱疹病毒的潜在致癌活性,最近已被证明在
对活动性 HCMV 感染的反应。此外,端粒酶抑制与显着的
降低 HCMV 实验室和临床毒株的病毒感染性。然而,端粒酶的意义
HCMV 病毒生命周期中的相关性以及这种关系的潜在治疗意义仍有待探索。
我们假设宿主端粒酶对于 HCMV 病毒生命周期很重要。我们首先要建立端粒酶
HCMV 感染后活性上调,端粒酶抑制后 HCMV 复制减少
使用多种端粒酶抑制方法对多种菌株和细胞系进行研究。端粒酶测定
药物端粒酶抑制剂 BIBR1532 和 MST-312 存在下的活性将建立
在实验室和临床菌株中端粒酶抑制后病毒感染性降低。随后的
使用诱导型遗传抑制剂,特别是针对 hTERT 的 siRNA 和诱导型 shRNA 构建体进行测定,
将测试病毒复制的减少是否是端粒酶抑制的结果,而不是脱靶效应。到
定义了 HCMV 上调端粒酶活性的作用机制,我们将评估端粒酶
关键病毒基因和相关基因异位表达和 shRNA 介导的敲低后的活性
产品将在感染和端粒酶抑制的感染条件下进行结合测定,以评估
通过 ChiP 和 QTIP 检测与 DNA 关联,通过 IP 和质谱与其他蛋白质关联。芯片
还将对宿主蛋白进行感染和端粒酶抑制感染条件下的检测
先前显示其影响端粒酶活性。为了定义端粒酶在病毒生命周期中的功能,我们
将进行端粒酶的不同时间抑制并评估其活性的病毒基因类别
受到端粒酶缺失的限制。总的来说,这些实验将建立潜在的临床
端粒酶与 HCMV 感染的相关性并定义 HCMV 的作用机制
上调端粒酶活性和端粒酶在病毒生命周期中的功能。增进了解
这些关系可能有助于深入了解其他疱疹病毒,为临床 HCMV 管理提供信息,并且
导致新的抗病毒疗法。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chloe M Cavanaugh其他文献
Chloe M Cavanaugh的其他文献
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{{ truncateString('Chloe M Cavanaugh', 18)}}的其他基金
Mechanism and Therapeutic Implication of Host Cell Telomerase Modulation by Human Cytomegalovirus
人巨细胞病毒调节宿主细胞端粒酶的机制和治疗意义
- 批准号:
10540730 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
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