A Human Sensory Neuron Model of VZV Infection
VZV 感染的人类感觉神经元模型
基本信息
- 批准号:9766418
- 负责人:
- 金额:$ 20.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcyclovirAddressAffectAfferent NeuronsAnimal ModelAntiviral AgentsApoptosisAutopsyBiological AssayBiologyBrainCellsCessation of lifeChickenpoxDNA VirusesDataDevelopmentEncephalitisEventExperimental ModelsExpression ProfilingFibroblastsGene Expression ProfilingGenetic TranscriptionHerpes zoster diseaseHerpesvirus Type 3HumanIn VitroIndividualInfectionLatent VirusLytic PhaseMAPK8 geneModelingMolecularMorbidity - disease rateMyelitisNervous system structureNeuraxisNeurologicNeuronsNeuropathogenesisPainPathogenesisPathway interactionsPhysically HandicappedPhysiologicalPopulationPositioning AttributePostherpetic neuralgiaPrimary InfectionRoleSensorySkinSpecies SpecificitySpecimenSpinal GangliaStem cellsSyndromeSystemTissuesTranscriptUrsidae FamilyVaccinationViralViral PathogenesisVirusVirus DiseasesVirus LatencyVirus ReplicationXenograft procedurebasecell typechronic paincognitive disabilitycostfetalhuman diseasehuman embryonic stem cellhuman modelhuman pluripotent stem cellin vitro Modelin vivoinduced pluripotent stem cellinsightlatency associated transcriptmortalitynerve stem cellnovel therapeuticspermissivenessprospective
项目摘要
Project Summary
New experimental models are needed to develop treatments for varicella zoster virus (VZV), a
DNA virus that has infected over 90% of individuals worldwide. Primary infection causes chickenpox,
while reactivation of the virus within the nervous system can have dire consequences. Shingles
(herpes zoster) is the most common manifestation of viral reactivation, affecting one out of every
three people in the U.S. and causing post-herpetic neuralgia (PHN), a severe, often chronic, pain
syndrome with annual U.S. costs of over $1 billion. Viral reactivation within the central nervous
system can result in encephalitis and myelitis, often leading to death or severe cognitive and physical
disability. Notably, VZV continues to exact a marked toll despite the advent and widespread use of
antiviral agents (acyclovir) and vaccination, which only afford partial protection and do not specifically
address PHN. Thus, new therapies are needed to limit the morbidity and mortality associated with
neuronal infection and reactivation.
The major limitation in the study of VZV infection is the strict species-specificity of the virus,
such that it essentially exclusively infects human cells. As a result, there are no robust animal models
that recapitulate essential features of human disease. Moreover, the virus appears to utilize distinct
cellular and molecular pathways in different cell types. Thus, studies of viral infection in human
fibroblasts or other skin cells may not directly bear on pathogenesis within human neurons. Recently,
VZV has been shown to infect neurons derived from human neural stem cells and human pluripotent
stem cells, suggesting that stem-cell based approaches for the study of VZV pathogenesis are likely
to hold great promise for the development of new treatments. However, most human neuronal
cultures systems derived from stem cells are typically comprised of few, if any, sensory neurons.
This is a great limitation since sensory neurons are the main cell type in which the virus establishes
latency and later re-emerges during reactivation.
Here, we propose to develop a model of human pluripotent stem cell based model of sensory
neuron infection by VZV. The establishment of such a model will result in the ability to study VZV
neuropathogenesis in a relevant cell type. We anticipate that establishment of our model will yield
initial insights into how VZV infects and reactivates in human sensory neurons and will serve as the
basis for a system to develop new treatments for VZV reactivation and PHN.
项目摘要
需要新的实验模型来开发水痘带状疱疹病毒(VZV)的治疗方法,
DNA病毒已经感染了全世界90%以上的人。初次感染会导致水痘,
而病毒在神经系统内的重新激活可能会产生可怕的后果。带状疱疹
(带状疱疹)是最常见的表现,病毒复活,影响一个每一个
在美国有三个人,并引起疱疹后神经痛(PHN),一种严重的,通常是慢性的疼痛
美国每年花费超过10亿美元的综合症。中枢神经系统内的病毒再活化
系统可导致脑炎和脑炎,通常导致死亡或严重的认知和身体
残疾。值得注意的是,VZV继续造成显著的死亡,尽管出现并广泛使用了
抗病毒药物(阿昔洛韦)和疫苗接种,只能提供部分保护,
地址PHN。因此,需要新的治疗方法来限制与糖尿病相关的发病率和死亡率。
神经元感染和再激活。
VZV感染研究的主要局限性是该病毒严格的种特异性,
使得它基本上只感染人类细胞。因此,没有可靠的动物模型
它概括了人类疾病的基本特征。此外,该病毒似乎利用不同的
不同细胞类型中的细胞和分子途径。因此,人类中病毒感染的研究
成纤维细胞或其它皮肤细胞可能不直接影响人神经元内的发病机制。最近,
VZV已被证明感染来自人神经干细胞和人多能干细胞的神经元。
干细胞,表明基于干细胞的VZV发病机制的研究方法是可能的
为新疗法的发展带来了巨大的希望。然而,大多数人类神经元
源自干细胞的培养系统通常由很少(如果有的话)的感觉神经元组成。
这是一个很大的限制,因为感觉神经元是病毒建立的主要细胞类型
潜伏期和稍后在重新激活期间重新出现。
在这里,我们建议开发一种基于人多能干细胞的感觉神经元模型。
VZV感染神经元。这一模型的建立将为研究VZV奠定基础
相关细胞类型中的神经发病机制。我们预计,我们的模型的建立将产生
初步了解VZV如何感染和重新激活人类感觉神经元,并将作为
为VZV再活化和PHN的新治疗方法的开发奠定了基础。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nectin-1 Is an Entry Mediator for Varicella-Zoster Virus Infection of Human Neurons
Nectin-1 是人类神经元水痘带状疱疹病毒感染的进入介质
- DOI:10.1128/jvi.01227-21
- 发表时间:2021
- 期刊:
- 影响因子:5.4
- 作者:Rajbhandari Labchan;Shukla Priya;Jagdish Balaji;Mandalla Abby;Li Qingxue;Ali Mir A.;Lee Hojae;Lee Gabsang;Sadaoka Tomohiko;Cohen Jeffrey I.;Venkatesan Arun
- 通讯作者:Venkatesan Arun
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ARUN VENKATESAN其他文献
ARUN VENKATESAN的其他文献
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{{ truncateString('ARUN VENKATESAN', 18)}}的其他基金
The Role of RanBP2 in the pathogenesis of acute necrotizing encephalopathy
RanBP2在急性坏死性脑病发病机制中的作用
- 批准号:
10190405 - 财政年份:2021
- 资助金额:
$ 20.47万 - 项目类别:
Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV
甲基苯丙胺和艾滋病毒对成人海马神经发生的损害
- 批准号:
7825349 - 财政年份:2007
- 资助金额:
$ 20.47万 - 项目类别:
Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV
甲基苯丙胺和艾滋病毒对成人海马神经发生的损害
- 批准号:
7230650 - 财政年份:2007
- 资助金额:
$ 20.47万 - 项目类别:
Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV
甲基苯丙胺和艾滋病毒对成人海马神经发生的损害
- 批准号:
8069174 - 财政年份:2007
- 资助金额:
$ 20.47万 - 项目类别:
Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV
甲基苯丙胺和艾滋病毒对成人海马神经发生的损害
- 批准号:
7409050 - 财政年份:2007
- 资助金额:
$ 20.47万 - 项目类别:
Impairment of Adult Hippocampal Neurogenesis by Methamphetamines and HIV
甲基苯丙胺和艾滋病毒对成人海马神经发生的损害
- 批准号:
7623132 - 财政年份:2007
- 资助金额:
$ 20.47万 - 项目类别:
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