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

• 批准号: 9253247
• 负责人: Paul R. Kinchington
• 金额: $ 46.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253247
• 关键词: Address; Adult; Affect; Afferent Neurons; Age; Anatomy; Animal Model; Antiviral Agents; Automobile Driving; Axonal Transport; Biology; Chickenpox; Chronic; Complication; Comprehension; DNA biosynthesis; Development; Disease; Elderly; Facial Pain; Funding; Ganglia; Gene Expression; Genetic Transcription; Glycine Receptors; Goals; HSV vector; Herpes zoster disease; Herpesviridae; Herpesvirus Type 3; Human; Hypersensitivity; Incidence; Infection; Life; Ligands; Mechanics; Mediating; Modeling; Nerve; Nervous system structure; Neurons; Orofacial Pain; Pain; Patients; Phosphotransferases; Population; Postherpetic neuralgia; Pre-Clinical Model; Process; Property; Proprioception; Proteins; Proteome; Public Health; Quality of life; Rattus; Receptor Activation; Risk; Severities; Signal Transduction; Simplexvirus; Specificity; Structure of trigeminal ganglion; Study models; System; Testing; Translating; Vibrissae; Viral; Viral Antigens; Viral Proteins; Virion; Virus Diseases; Virus Replication; allodynia; base; chronic pain; experience; genetic regulatory protein; improved; indexing; innovation; mutant; pain behavior; pre-clinical; prevent; programs; promoter; protein expression; public health relevance; receptor; receptor expression; recombinant virus; response; therapeutic gene; treatment strategy; varicella-zoster virus immediate early protein 62; vector; viral DNA

 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的、极其痛苦和令人衰弱的并发症，当水痘带状疱疹病毒（VZV）从潜伏期重新激活时，很难治疗。宿主感觉神经元，全世界多达三分之一的成年人面临带状疱疹和 PHN 的发病率和严重程度随着年龄的增长而增加，而且可能如此。因此，PHN 仍然是一个紧迫的公共卫生问题。针对 FOA PA-13-118，我们扩展了一个临床前模型。 PHN，将 VZV 接种到大鼠足垫中会引起长时间的疼痛症状，这与人类 PHN 的情况相似。我们现在扩展了该模型，以显示放置在胡须垫和三叉神经上的 VZV 产生的疼痛。我们建议，对这些模型的研究将使我们能够了解 VZV 如何与神经系统相互作用以引起疼痛，并测试改进的治疗方法。在目标 1 中，我们将定义 VZV 需要做什么。我们将检验以下假设：有限的 VZV 表达程序不需要有效复制，这可能反映了带状疱疹后的人类神经节，其中足够的病毒表达而没有完全复制会引发导致 PHN 的变化。我们将重点关注 VZV IE62 调节蛋白驱动疼痛的机制：IE62 存在于疼痛大鼠的神经节神经元中。第三，我们将研究为什么缺乏 ORF47 激酶的 VZV 不会诱发慢性疼痛，并检验这一假设。 ORF47 是启动神经元感染所必需的，目标 2 将确定疼痛是否仅由 VZV 感染和表达 VZV 蛋白的神经元传播，或者包括由其他过程改变的神经元。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，然后我们将使用 IE62 蛋白来解决哪些神经元亚型发出慢性疼痛信号。复制缺陷型 HSV (rdHSV) 载体中的神经元特异性启动子将通过 rdHSV 转录靶向特定神经元群体，寻求改善并更有效地治疗 VZV 引起的大鼠疼痛状态。这不仅可以提供更长或更具体的缓解 VZV 引起的疼痛的方法，而且还可以提供有关引起疼痛的神经元类型的信息，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患有 PHN 及其后果的带状疱疹患者。