Mechanisms of blood-brain barrier disruption by an encephalitic virus
脑炎病毒破坏血脑屏障的机制
基本信息
- 批准号:8449166
- 负责人:
- 金额:$ 45.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-05-01 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAdenovirusesAstrocytesBasic ScienceBiological AssayBiological ModelsBlood - brain barrier anatomyBrainCapsidCapsid ProteinsCellsCentral Nervous System DiseasesCleaved cellCultured CellsCytoskeletonDNADNA Sequence RearrangementDNA VirusesDataDevelopmentDiseaseDrug Delivery SystemsEncephalitisEndothelial CellsFamilyFiberGeneticGoalsHomeostasisHumanImmuneImmune responseImmunologyIn SituIn VitroInfectionInfectious AgentInfiltrationInflammatoryIntegrinsIntercellular JunctionsKnock-outKnowledgeLeadLeukocytesMatrix MetalloproteinasesMicrogliaMissionModelingMolecularMolecular and Cellular BiologyMorbidity - disease rateMusMutant Strains MiceNatural ImmunityNeurobiologyOutcomePathogenesisPathway interactionsPatternPermeabilityPhysiologicalPlayProteinsProteolysisPublic HealthPublishingRNA VirusesResearchResistanceRetroviridaeRoleSignal PathwaySignal TransductionSystemTestingTherapeutic InterventionTight JunctionsToxinUnited States National Institutes of HealthVascular Endothelial CellViralViral EncephalitisViral GenesViral ProteinsVirionVirusVirus DiseasesWorkbaseburden of illnesscell typechemokinecytokineimprovedin vivoin vivo Modelinhibitor/antagonistinnovationinsightknockout genemembermortalitymutantparticlepathogenpreventprotein expressionpublic health relevancevirus host interaction
项目摘要
DESCRIPTION (provided by applicant): Viral encephalitis is a potentially deadly sequela of viral infection for which there are few treatment options. It is frequently associated with blood-brain barrier (BBB) disruption, enabling the entry of virus, inflammatory cells, and deleterious molecules into the brain parenchyma. Members of at least eleven virus families cause encephalitis, including DNA viruses, retroviruses and RNA viruses, with significant morbidity and mortality. Little is known about the mechanisms by which viral infections disrupt the BBB, including the specific viral genes involved and how viruses manipulate host functions that contribute to this important protective barrier. The long-term goal of this research is to improve therapy for people with encephalitis by understanding how viral gene products interact with the host to cause the disease. The overall objective of this application is to determine how a natural mouse pathogen that causes encephalitis, mouse adenovirus type 1 (MAV-1), disrupts the BBB. The central hypothesis is that one or more viral factors induce altered expression and/or function of endothelial cell tight junction proteins, leading to disruption of the BBB. The rationale is that once the mechanism of MAV-1 disruption of the BBB is known, the system can be manipulated genetically and pharmacologically in mice, resulting in innovative approaches for the treatment of encephalitides in humans. The hypothesis will be tested with two specific aims: 1) Identify the primary virus-induced host response leading to altered tight junction protein expression during MAV-1 infection, and 2) Identify the innate signaling and viral components responsible for destruction of BBB integrity. Aim 1 is based on published and preliminary data that MAV-1 reduces tight junction protein expression in brain endothelial cells and increases matrix metalloproteinase (MMP) expression in brains, astrocytes and microglia. Established assays for BBB permeability, MMP activity, and transendothelial resistance will be used to test the hypothesis that MMPs play a role in the decrease in tight junction proteins during infection. Gene knockout-, inhibitor-treated-, and leukocyte-depleted mice will be used to extend these findings in vivo. In Aim 2, viral mutants and physically altered virus particles will be used in in vivo and in vitro infections to test the hypothesis that viral components serve as pathogen-associated molecular patterns that signal innate immunity. To identify which innate immune signaling pathway(s) MAV-1 triggers, leading to BBB disruption, an ordered approach using infection of mouse gene knockouts will be employed. The proposed research is innovative because it uses a comprehensive approach to study BBB disruption caused by a viral pathogen in its natural host, addressing both viral and host contributions to encephalitis. This research will be significant because it will be the first viral mechanism of BBB disruption characterized in vivo in a natural host, contributing an understanding of the action of specific viral gene products and mammalian innate immunity on BBB function. This powerful mouse/MAV-1 model can be manipulated to evaluate innovative approaches to the treatment of encephalitis.
描述(由申请人提供):病毒性脑炎是病毒感染的一种潜在致命后遗症,目前几乎没有治疗选择。它通常与血脑屏障 (BBB) 破坏有关,使病毒、炎症细胞和有害分子进入脑实质。至少有 11 个病毒家族的成员可引起脑炎,包括 DNA 病毒、逆转录病毒和 RNA 病毒,具有显着的发病率和死亡率。人们对病毒感染破坏血脑屏障的机制知之甚少,包括涉及的特定病毒基因以及病毒如何操纵宿主功能,从而有助于这一重要的保护屏障。这项研究的长期目标是通过了解病毒基因产物如何与宿主相互作用从而导致脑炎疾病,从而改善对脑炎患者的治疗。该应用的总体目标是确定引起脑炎的天然小鼠病原体,即 1 型小鼠腺病毒 (MAV-1),如何破坏 BBB。中心假设是一种或多种病毒因子诱导内皮细胞紧密连接蛋白的表达和/或功能改变,从而导致血脑屏障的破坏。基本原理是,一旦了解了 MAV-1 破坏 BBB 的机制,就可以在小鼠体内通过遗传和药理学方法对该系统进行操作,从而产生治疗人类脑炎的创新方法。该假设将通过两个具体目标进行测试:1)确定导致 MAV-1 感染期间紧密连接蛋白表达改变的主要病毒诱导的宿主反应,以及 2)确定导致 BBB 完整性破坏的先天信号传导和病毒成分。目标 1 基于已发表的初步数据,即 MAV-1 降低脑内皮细胞中的紧密连接蛋白表达,并增加大脑、星形胶质细胞和小胶质细胞中的基质金属蛋白酶 (MMP) 表达。已建立的 BBB 通透性、MMP 活性和跨内皮阻力测定法将用于检验 MMP 在感染过程中紧密连接蛋白减少中发挥作用的假设。基因敲除、抑制剂处理和白细胞去除的小鼠将用于在体内扩展这些发现。在目标 2 中,病毒突变体和物理改变的病毒颗粒将用于体内和体外感染,以测试病毒成分作为发出先天免疫信号的病原体相关分子模式的假设。为了确定 MAV-1 触发哪种先天免疫信号通路,导致 BBB 破坏,将采用使用小鼠基因敲除感染的有序方法。拟议的研究具有创新性,因为它采用综合方法来研究病毒病原体在其自然宿主中引起的血脑屏障破坏,解决病毒和宿主对脑炎的影响。这项研究意义重大,因为它将是第一个在自然宿主体内表征的 BBB 破坏的病毒机制,有助于了解特定病毒基因产物和哺乳动物先天免疫对 BBB 功能的作用。这种强大的小鼠/MAV-1 模型可用于评估治疗脑炎的创新方法。
项目成果
期刊论文数量(0)
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Katherine R. Spindler其他文献
Katherine R. Spindler的其他文献
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{{ truncateString('Katherine R. Spindler', 18)}}的其他基金
Viral interaction with host eIF2alpha kinases
病毒与宿主 eIF2α 激酶的相互作用
- 批准号:
9976443 - 财政年份:2018
- 资助金额:
$ 45.76万 - 项目类别:
Viral interaction with host eIF2alpha kinases
病毒与宿主 eIF2α 激酶的相互作用
- 批准号:
10459361 - 财政年份:2018
- 资助金额:
$ 45.76万 - 项目类别:
Viral interaction with host eIF2alpha kinases
病毒与宿主 eIF2α 激酶的相互作用
- 批准号:
9789821 - 财政年份:2018
- 资助金额:
$ 45.76万 - 项目类别:
American Society for Virology Meeting - Jr. Investigator Support Proposal
美国病毒学学会会议 - 初级研究员支持提案
- 批准号:
9932318 - 财政年份:2011
- 资助金额:
$ 45.76万 - 项目类别:
Mechanisms of blood-brain barrier disruption by an encephalitic virus
脑炎病毒破坏血脑屏障的机制
- 批准号:
8651867 - 财政年份:2011
- 资助金额:
$ 45.76万 - 项目类别:
American Society for Virology Meeting- Jr Investigator Support
美国病毒学学会会议 - 初级研究者支持
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10623137 - 财政年份:2011
- 资助金额:
$ 45.76万 - 项目类别:
Mechanisms of blood-brain barrier disruption by an encephalitic virus
脑炎病毒破坏血脑屏障的机制
- 批准号:
8183521 - 财政年份:2011
- 资助金额:
$ 45.76万 - 项目类别:
Mechanisms of blood-brain barrier disruption by an encephalitic virus
脑炎病毒破坏血脑屏障的机制
- 批准号:
8260848 - 财政年份:2011
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克隆小鼠腺病毒易感性主要基因
- 批准号:
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- 资助金额:
$ 45.76万 - 项目类别:
Cloning a major gene for mouse adenovirus susceptibility
克隆小鼠腺病毒易感性主要基因
- 批准号:
7753149 - 财政年份:2006
- 资助金额:
$ 45.76万 - 项目类别:
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