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

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the identification of specific viral mechanisms leading to disruption of the blood-brain barrier will increase understanding of the pathogenesis of viral encephalitis. Blood-brain barrier disruption is also observed in non-viral disease of the central nervous system (CNS). In addition, a functional barrier is a significant block to effective drug delivery. This research is ultimately expected to facilitate development of pharmacological approaches to treat both viral encephalitis and other CNS disease. Thus it addresses the NIH mission to reduce the burdens of illness.
描述(由申请人提供):病毒性脑炎是病毒感染的潜在致命续集,几乎没有治疗选择。它经常与血脑屏障(BBB)破坏有关,使病毒,炎症细胞和有害分子进入脑实质。至少11个病毒家族的成员引起脑炎,包括DNA病毒,逆转录病毒和RNA病毒,具有明显的发病率和死亡率。关于病毒感染破坏BBB的机制知之甚少,包括所涉及的特定病毒基因以及病毒如何操纵宿主功能,从而有助于这种重要的保护性屏障。这项研究的长期目标是通过了解病毒基因产品如何与宿主相互作用以引起疾病来改善脑炎患者的治疗。该应用的总体目的是确定导致脑炎的天然小鼠病原体如何破坏BBB。中心假设是一个或多个病毒因素诱导内皮细胞紧密连接蛋白的表达和/或功能改变,导致BBB破坏。理由是,一旦已知MAV-1破坏BBB的机制,就可以在小鼠中对该系统进行遗传和药理操作,从而导致了对人类脑磷脂治疗的创新方法。该假设将以两个具体的目的进行检验:1)确定原发性病毒诱导的宿主反应,导致MAV-1感染期间紧密的连接蛋白表达改变,以及2)确定固有信号传导和病毒成分负责破坏BBB完整性。 AIM 1基于已发表和初步数据,该数据可降低脑内皮细胞中紧密的连接蛋白表达,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。建立的BBB渗透性,MMP活性和跨内皮抗性的测定法将用于检验以下假设:MMP在感染过程中紧密连接蛋白的降低中起作用。基因基因敲除,抑制剂治疗和白细胞缺失的小鼠将使用体内扩展这些发现。在AIM 2中,病毒突变体和身体改变的病毒颗粒将用于体内和体外感染,以检验病毒成分作为病原体相关的分子模式的假设,这些分子模式表明了先天免疫。为了确定哪些先天免疫信号通路(S)MAV-1触发器,导致BBB破坏,将采用一种使用小鼠基因敲除的有序方法。拟议的研究具有创新性,因为它使用一种全面的方法来研究其自然宿主中病毒病原体引起的BBB破坏,从而解决了病毒式和宿主对脑炎的贡献。这项研究将是重要的,因为它将是在天然宿主中体内特征的BBB中断的第一种病毒机制,从而有助于理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。可以操纵这种强大的小鼠/MAV-1模型,以评估脑炎治疗的创新方法。 公共卫生相关性:拟议的研究与公共卫生有关,因为鉴定导致血脑屏障中断的特定病毒机制将增加对病毒脑炎发病机理的理解。在中枢神经系统(CNS)的非病毒疾病中也观察到血脑屏障破坏。此外,功能性障碍是有效递送药物的重要障碍。最终,这项研究最终有助于开发用于治疗病毒脑炎和其他中枢神经系统疾病的药理方法。因此,它解决了减少疾病负担的NIH任务。

项目成果

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数据更新时间:2024-06-01

Katherine R. Spind...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
    9976443
  • 财政年份:
    2018
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
    10459361
  • 财政年份:
    2018
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
    9789821
  • 财政年份:
    2018
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
    9932318
  • 财政年份:
    2011
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
    8651867
  • 财政年份:
    2011
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
  • 批准号:
    10623137
    10623137
  • 财政年份:
    2011
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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:
    8449166
    8449166
  • 财政年份:
    2011
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
    8260848
  • 财政年份:
    2011
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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:
    7846601
    7846601
  • 财政年份:
    2009
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 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
    7753149
  • 财政年份:
    2006
  • 资助金额:
    $ 53.29万
    $ 53.29万
  • 项目类别:

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脑炎病毒破坏血脑屏障的机制
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