Molecular Mechanisms of Sleep Responses to Viral Infection

睡眠对病毒感染反应的分子机制

基本信息

  • 批准号:
    7599724
  • 负责人:
  • 金额:
    $ 30.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-04-15 至 2012-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Influenza is a respiratory viral infection often accompanied by severe symptoms such as high fevers and a profound need to sleep. Collectively, these symptoms are part of the acute phase response (APR). The understanding of the molecular mediators of the viral APR is in its infancy. Some of the progress made in deciphering centrally regulated APRs resulted from research supported by this grant. Our accomplishments include; showing that sleep changes over the course of an influenza virus infection; demonstrating that a toxic viral by-product, double-stranded (ds) RNA, is found in lungs of infected mice and that it induces the APR; characterizing the influenza APR in mice, and investigating APR molecular mechanisms through development of appropriate infection models and using genetically-deficient mice. Most importantly, we recently demonstrated that strains of human influenza .previously considered incapable of accessing the mouse brain, in fact do so within a few hours following intranasal infection. In brain, viral RNA and viral antigen are accompanied by induction of cytokines with the potential for mediating the APR. We expand upon these data in Aims 1 and 2. Aim 1 addresses the general hypothesis that virus, viral proteins and/or viral RNA pass from the nasal cavities to the olfactory bulb (OB) via the olfactory nerve and induce cytokine production. We will use immunohistochemistry, polymerase chain reaction techniques, and electron microscopy to determine the time course of viral invasion of the OB and its relationship to cytokine expression. Double-labeling techniques will be used to determine co-localization of virus protein with cytokines and the cell types expressing cytokines and containing virus proteins. Aim 2 tests the hypothesis that OB-expressed cytokines activate hypothalamic (HT) cytokines and subsequent HT-regulated APRs. The timing of HT cytokine expression relative to OB expression will be determined. The effects of TNFa injection into the OB and the effects of cutting OB-brain connections on HT-cytokine and sleep and fever responses will be determined. Aim 3 tests the general hypothesis that invasion of the CNS by influenza virus is affected by immune status of the host. We determine whether homologous immunity to influenza virus offers partial protection against viral invasion of the brain. The measures made in Aim 1 will be used in Aims 2 and 3 along with sleep, body temperature, locomotor activity and body weight determinations. Aim 4 is derived from our past work showing that viral dsRNA induces flu-like symptoms. Thus mice deficient in toll- like receptor 3 (TLR3), a receptor that binds dsRNA, will be challenged with virus. APRs including sleep and brain cytokine expression will be determined. There is an association between upper respiratory viral infections and sudden infant death syndrome (SIDS); SIDS occurs during sleep and is associated with sleep abnormalities. The proposed work will provide insights into how viruses induce disease symptoms as well as such complications as SIDS and viral encephalitis/encephalopathy.
描述(由申请人提供):流感是一种呼吸道病毒感染,通常伴有严重症状,如高烧和严重的睡眠需求。总的来说,这些症状是急性期反应(APR)的一部分。对病毒性APR的分子介质的理解还处于起步阶段。在破译中央监管的年利率方面取得的一些进展是由该赠款支持的研究成果。我们的成就包括:显示睡眠在流感病毒感染的过程中发生变化;证明在感染小鼠的肺中发现有毒的病毒副产物双链(ds)RNA,并且其诱导APR;表征小鼠中的流感APR,并且通过开发适当的感染模型和使用遗传缺陷小鼠来研究APR分子机制。最重要的是,我们最近证明,以前被认为不能进入小鼠大脑的人流感病毒株,实际上在鼻内感染后几小时内就能进入小鼠大脑。在脑中,病毒RNA和病毒抗原伴随着具有介导APR潜力的细胞因子的诱导。我们在目标1和2中扩展了这些数据。目的1阐述了病毒、病毒蛋白和/或病毒RNA通过嗅神经从鼻腔进入嗅球(OB)并诱导细胞因子产生的一般假设。我们将使用免疫组化,聚合酶链反应技术,和电子显微镜,以确定OB的病毒入侵的时间过程及其与细胞因子表达的关系。将使用双标记技术来确定病毒蛋白与细胞因子的共定位以及表达细胞因子并含有病毒蛋白的细胞类型。目的2验证OB表达的细胞因子激活下丘脑(HT)细胞因子和随后的HT调节的APR的假设。将确定HT细胞因子表达相对于OB表达的时间。将确定将TNFa注射到OB中的影响以及切断OB-脑连接对HT-细胞因子和睡眠及发热反应的影响。目的3检验流感病毒侵入中枢神经系统受宿主免疫状态影响的一般假设。我们确定是否同源免疫流感病毒提供部分保护,防止病毒入侵的大脑。在目标1中进行的测量将用于目标2和目标3沿着以及睡眠、体温、自发活动和体重测定。目的4来自我们过去的工作,表明病毒dsRNA诱导流感样症状。因此,缺乏Toll样受体3(TLR 3)(一种结合dsRNA的受体)的小鼠将受到病毒的攻击.将确定包括睡眠和脑细胞因子表达在内的APR。上呼吸道病毒感染与婴儿猝死综合征(SIDS)之间存在关联; SIDS发生在睡眠期间,与睡眠异常有关。拟议的工作将提供深入了解病毒如何引起疾病症状以及并发症,如SIDS和病毒性脑炎/脑病。

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)
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JAMES Martin KRUEGER其他文献

JAMES Martin KRUEGER的其他文献

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{{ truncateString('JAMES Martin KRUEGER', 18)}}的其他基金

TNF signaling methods initiating in vitro sleep-like states
启动体外类睡眠状态的 TNF 信号转导方法
  • 批准号:
    9232403
  • 财政年份:
    2016
  • 资助金额:
    $ 30.77万
  • 项目类别:
TNF signaling methods initiating in vitro sleep-like states
启动体外类睡眠状态的 TNF 信号转导方法
  • 批准号:
    9327075
  • 财政年份:
    2016
  • 资助金额:
    $ 30.77万
  • 项目类别:
Molecular Mechanisms of Sleep Responses to Viral Infection
睡眠对病毒感染反应的分子机制
  • 批准号:
    7802843
  • 财政年份:
    2007
  • 资助金额:
    $ 30.77万
  • 项目类别:
Molecular Mechanisms of Sleep Responses to Viral Infection
睡眠对病毒感染反应的分子机制
  • 批准号:
    8056508
  • 财政年份:
    2007
  • 资助金额:
    $ 30.77万
  • 项目类别:
Molecular Mechanisms of Sleep Responses to Viral Infection
睡眠对病毒感染反应的分子机制
  • 批准号:
    7251734
  • 财政年份:
    2007
  • 资助金额:
    $ 30.77万
  • 项目类别:
Molecular Mechanisms of Sleep Responses to Viral Infection
睡眠对病毒感染反应的分子机制
  • 批准号:
    7406113
  • 财政年份:
    2007
  • 资助金额:
    $ 30.77万
  • 项目类别:
CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF THYROID HORMONE DIESEASE
甲状腺激素疾病的中枢神经系统表现
  • 批准号:
    6306308
  • 财政年份:
    1999
  • 资助金额:
    $ 30.77万
  • 项目类别:
CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF THYROID HORMONE DIESEASE
甲状腺激素疾病的中枢神经系统表现
  • 批准号:
    6219763
  • 财政年份:
    1999
  • 资助金额:
    $ 30.77万
  • 项目类别:
MECHANISMS OF SLEEP RESPONSES TO VIRAL INFECTIONS
睡眠对病毒感染的反应机制
  • 批准号:
    2643547
  • 财政年份:
    1997
  • 资助金额:
    $ 30.77万
  • 项目类别:
MECHANISMS OF SLEEP RESPONSES TO VIRAL INFECTIONS
睡眠对病毒感染的反应机制
  • 批准号:
    6181747
  • 财政年份:
    1997
  • 资助金额:
    $ 30.77万
  • 项目类别:

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  • 批准号:
    3477337
  • 财政年份:
    1988
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NEUROPEPTIDERGIC MEDIATION OF THE ACUTE PHASE REACTION
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