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

 描述(由申请人提供)：带状疱疹后遗神经痛(PHN)仍然是一种常见的、极其痛苦和令人衰弱的并发症，难以治疗。当疱疹病毒水痘-带状疱疹病毒(VZV)在宿主感觉神经元内潜伏重新激活时，Zostr和PHN就会发生，全世界多达三分之一的成年人面临风险。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，可能严重到严重降低生活质量的地步。因此，PHN仍然是一个紧迫的公共卫生问题。VZV引起持久疼痛的机制尚不清楚。作为对FOA PA-13-118的反应，我们扩展了PHN的临床前模型，在该模型中，VZV接种到大鼠足垫中可以诱导长时间的疼痛迹象，这反映了人类PHN的各个方面。我们现在已经扩展了模型，以显示疼痛是由放置在胡须垫和三叉神经节的VZV产生的。我们认为，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来引发疼痛，并测试改进的治疗方法。在目标1中，我们将定义VZV在导致疼痛的大鼠身上需要产生什么。我们将测试这一假设，即有限的VZV表达程序在不需要生产性复制的情况下就足够了。这可能反映了人类带状疱疹后的神经节，在这种情况下，病毒表达而不完全复制会触发变化，导致慢性疼痛。众所周知，PHN对抗病毒药物没有反应。我们将重点研究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不会引起慢性疼痛，验证ORF47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蛋白表达的神经元传递，还是包括VZV感染或病毒蛋白表达以外的过程改变的神经元。我们将开发一种创新的基于配体依赖的甘氨酸受体表达系统来停止表达甘氨酸受体的神经元的放电。然后，我们将利用复制缺陷单纯疱疹病毒(RdHSV)载体中的神经元特异性启动子，研究IE62蛋白诱导的慢性疼痛的神经元亚型。目的3将寻求改善和更有效地治疗VZV诱导的大鼠疼痛状态，通过寻求以rdHSV载体转录为靶点的特定神经元群体来减轻疼痛。这不仅可能为VZV引起的疼痛提供更长时间或更具体的缓解，还将提供有关引起疼痛的神经元类型的信息。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，然后这种疼痛可以应用于那些不幸遭受PHN及其后果的带状疱疹患者。

 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.