Varicella zoster virus Induced Pain in a Rat Model of Post Herpetic Neuralgia

水痘带状疱疹病毒在带状疱疹后神经痛大鼠模型中引起疼痛

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Post-Herpetic Neuralgia (PHN) remains a common, exceedingly painful and debilitating complication of Herpes Zoster that is difficult to treat. Zostr and PHN occur when the herpesvirus varicella-zoster virus (VZV) reactivates from latency within host sensory neurons, and up to one third of adults worldwide are at risk. Incidence and severity of Zoster and PHN increase with age, and may be so severe as to profoundly reduce quality of life. As such, PHN remains a pressing public health concern. The mechanisms by which VZV causes prolonged pain are not understood. In response to FOA PA-13-118, we expand a pre-clinical model of PHN, where VZV inoculated into the rat footpad induces prolonged signs of pain that mirror aspects of human PHN. We have now expanded the model to show pain develops from VZV placed at the whisker pad and trigeminal ganglia. We propose that our study of these models will enable us to gain comprehension of how VZV interacts with the nervous system to induce pain, and test improved treatments. In Aim 1, we will define what is needed to be made by VZV in the rat leading to pain. We will test the hypothesis that a limited VZV expression program is sufficient without need for productive replication. This may reflect human ganglia after zoster, in which viral expression without full replication triggers changes leading t chronic pain. PHN is notoriously unresponsive to antivirals. We will focus on mechanisms by which the VZV IE62 regulatory protein drives pain: IE62 is found in ganglionic neurons of rats with pain. Third, we will investigate why VZV lacking the ORF47 kinase does not induce chronic pain, testing the hypothesis that ORF47 is needed to initiate neuronal infection. Aim 2 will determine if pain is transmitted only by VZV infected and VZV protein-expressing neurons, or includes neurons altered by processes other than VZV infection or viral protein expression. We will exploit an innovative ligand-dependent glycine receptor expression-based system to stop firing of neurons in which receptor is expressed. We will then address what neuron subtypes signal chronic pain induced by the IE62 protein, using neuron-specific promoters in replication defective HSV (rdHSV) vectors. Aim 3 will seek to improve and more effectively treat the VZV-induced pain state in the rat, by seeking to transcriptionally target specific neuron populations with rdHSV vectors that reduce pain. This may not only provide longer or more specific relief of VZV-induced pain, but will provide information on types of neurons inducing pain. Together, our approaches have potential to revolutionize the way we think about VZV induced pain, which can be then applied to those with zoster unfortunate to suffer PHN and its consequences.
 描述(由申请人提供):带状疱疹后神经痛(PHN)仍然是带状疱疹的一种常见、极度疼痛和使人虚弱的并发症,难以治疗。带状疱疹和PHN发生于疱疹病毒水痘带状疱疹病毒(VZV)从宿主感觉神经元内的潜伏期重新激活时,全球多达三分之一的成年人处于风险中。带状疱疹和PHN的发病率和严重程度随年龄增长而增加,严重时可严重降低生活质量。因此,PHN仍然是一个紧迫的公共卫生问题。VZV引起长期疼痛的机制尚不清楚。为了响应FOA PA-13-118,我们扩展了PHN的临床前模型,其中接种到大鼠足垫中的VZV诱导反映人类PHN方面的长期疼痛体征。我们现在扩展了模型,以显示放置在须垫和三叉神经节处的VZV引起的疼痛。我们建议我们对这些模型的研究将使我们能够理解VZV如何与神经系统相互作用以诱导疼痛,并测试改进的治疗方法。在目标1中,我们将定义VZV在大鼠中需要产生什么样的疼痛。我们将测试的假设,一个有限的VZV表达程序是足够的,而不需要生产性复制。这可能反映了带状疱疹后的人类神经节,其中没有完全复制的病毒表达触发了导致慢性疼痛的变化。众所周知,PHN对抗病毒药物无反应。我们将重点关注VZV IE62调节蛋白驱动疼痛的机制:IE62在疼痛大鼠的神经节神经元中发现。第三,我们将研究为什么缺乏ORF 47激酶的VZV不会引起慢性疼痛,测试ORF 47是启动神经元感染所必需的假设。目的2将确定疼痛是否仅由VZV感染和VZV蛋白表达神经元传递,或包括由VZV感染或病毒蛋白表达以外的过程改变的神经元。我们将利用一种创新的基于配体依赖性甘氨酸受体表达的系统来停止表达受体的神经元的放电。然后,我们将解决什么样的神经元亚型信号慢性疼痛诱导的IE62蛋白,使用复制缺陷型HSV(rdHSV)载体中的神经元特异性启动子。目的3将寻求通过寻求用减轻疼痛的rdHSV载体转录靶向特定神经元群体来改善和更有效地治疗大鼠中VZV诱导的疼痛状态。这不仅可以提供更长或更具体的缓解VZV诱导的疼痛,但将提供有关类型的神经元诱导疼痛的信息。总之,我们的方法有可能彻底改变我们对VZV引起的疼痛的看法,然后可以应用于那些不幸遭受PHN及其后果的带状疱疹患者。

项目成果

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Paul R. Kinchington其他文献

Paul R. Kinchington的其他文献

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{{ truncateString('Paul R. Kinchington', 18)}}的其他基金

VZV vaccine attenuation and the DNA damage response
VZV 疫苗减毒和 DNA 损伤反应
  • 批准号:
    10657725
  • 财政年份:
    2022
  • 资助金额:
    $ 46.63万
  • 项目类别:
Role of VZV Latency Transcript (VLT) and ORF63 in latency and reactivation
VZV 潜伏转录本 (VLT) 和 ORF63 在潜伏和重新激活中的作用
  • 批准号:
    10570901
  • 财政年份:
    2020
  • 资助金额:
    $ 46.63万
  • 项目类别:
Role of VZV Latency Transcript (VLT) and ORF63 in latency and reactivation
VZV 潜伏转录本 (VLT) 和 ORF63 在潜伏和重新激活中的作用
  • 批准号:
    10550430
  • 财政年份:
    2020
  • 资助金额:
    $ 46.63万
  • 项目类别:
Varicella zoster virus-Induced Pain in a Rat Model of Post-Herpetic Neuralgia
带状疱疹病毒引起的带状疱疹后神经痛大鼠模型疼痛
  • 批准号:
    9011769
  • 财政年份:
    2015
  • 资助金额:
    $ 46.63万
  • 项目类别:
Molecular studies of VZV infection, latency and reactivation in human neurons in-vitro
人类神经元水痘带状疱疹病毒感染、潜伏期和再激活的分子研究
  • 批准号:
    9179591
  • 财政年份:
    2015
  • 资助金额:
    $ 46.63万
  • 项目类别:
Molecular studies of VZV infection, latency and reactivation in human neurons in-vitro
人类神经元水痘带状疱疹病毒感染、潜伏期和再激活的分子研究
  • 批准号:
    9052861
  • 财政年份:
    2015
  • 资助金额:
    $ 46.63万
  • 项目类别:
A new in vitro neuron model of axonal transport and persistence of varicella zost
水痘带状疱疹轴突运输和持续性的新体外神经元模型
  • 批准号:
    8487903
  • 财政年份:
    2013
  • 资助金额:
    $ 46.63万
  • 项目类别:
A new in vitro neuron model of axonal transport and persistence of varicella zost
水痘带状疱疹轴突运输和持续性的新体外神经元模型
  • 批准号:
    8606907
  • 财政年份:
    2013
  • 资助金额:
    $ 46.63万
  • 项目类别:
Varicella zoster virus-Induced Pain in a Rat Model of Post-Herpetic Neuralgia
带状疱疹病毒引起的带状疱疹后神经痛大鼠模型疼痛
  • 批准号:
    7848656
  • 财政年份:
    2009
  • 资助金额:
    $ 46.63万
  • 项目类别:
Varicella zoster virus-Induced Pain in a Rat Model of Post-Herpetic Neuralgia
带状疱疹病毒引起的带状疱疹后神经痛大鼠模型疼痛
  • 批准号:
    7563123
  • 财政年份:
    2009
  • 资助金额:
    $ 46.63万
  • 项目类别:

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