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
• 负责人: Paul R. Kinchington
• 金额: $ 53.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011769
• 关键词: Absence of pain sensation; Address; Adult; Affect; Afferent Neurons; Age; Aging; Animal Model; Antiviral Therapy; Automobile Driving; Behavior; Biology; Chickenpox; Chronic; Complication; Comprehension; Data; Development; Disease; Elderly; Engineering; Funding; Ganglia; Glycine Receptors; Goals; HSV vector; HSV-1 vector; Health; Herpes zoster disease; Herpesviridae; Herpesvirus Type 3; Human; Incidence; Infection; Lead; Ligands; Mediating; Modeling; Nerve; Nervous system structure; Neurons; Pain; Patients; Persistent pain; Phosphotransferases; Postherpetic neuralgia; Property; Protein Kinase; Proteins; Proteome; Public Health; Quality of life; Rattus; Receptor Activation; Recombinants; Reporting; Repression; Risk; Role; Signal Transduction; Simplexvirus; Societies; Specificity; System; Testing; Thermal Hyperalgesias; Transcription Coactivator; Transcriptional Activation; Viral Antigens; Viral Proteins; Virion; Virus Replication; allodynia; chronic pain; clinically relevant; experience; genetic regulatory protein; improved; indexing; innovation; mechanical allodynia; mutant; pain behavior; prevent; promoter; protein expression; response; therapeutic gene; treatment strategy; varicella-zoster virus immediate early protein 62; vector control

 DESCRIPTION (provided by applicant): Post-Herpetic Neuralgia (PHN) is a common, exceedingly painful and debilitating complication of Herpes Zoster that is difficult to treat and i unmet in the need for improved therapies. Zoster and PHN occur when varicella-zoster virus (VZV) reactivates from a latent state that was established in host sensory neurons during chickenpox. Most adults worldwide are at risk for Zoster, PHN and pain, which may be so severe as to profoundly reduce quality of life. Incidence increases with age, and our aging society implies Zoster and PHN may become even more pressing public health concerns. The mechanisms by which VZV causes persistent pain are not understood. This project, directed to FOA PA-13-118, expands a clinically relevant model of PHN in which VZV inoculated into the rat footpad induces prolonged mechanical allodynia and thermal hyperalgesia. Our overlying hypothesis is that this model will provide better comprehension of how VZV interacts with the nervous system to induce pain, and be a platform to test improved approaches for treatment of VZV-induced pain. Aim 1 will define the requirements of VZV expression and replication in the rat to induce pain. We will test the hypothesis that limited VZV expression is sufficient to drive chronic indicators of pain in the absence of productive replication. We will also test the hypothesis that VZV lacking the ORF47 kinase, which does not induce chronic pain, cannot initiate infection of the rat required for pain. Third, we will address the intrinsic properties by which the VZV IE62 transcriptional regulator induces chronic pain behaviors independent of other VZV proteins. These studies will establish the key components of VZV replication and expression in driving the pain state in the model. Aim 2 will focus on the role of infected neurons in contributing to the pain state. We will test the hypothesis that VZV protein expressing neurons directly drive nocifensive behaviors, exploiting an innovative ligand-dependent, neuron- specific pain repression system that involves expression of glycine receptors and activation by ligands. We will also address the neuron subtypes involved in driving a pain state that is induced by specific VZV pain-inducing proteins expressed from neuron-specific promoters in replication defective HSV (rdHSV) vectors. This could also establish a more prolonged model of VZV-induced pain behaviors. Aim 3 will address improved and more specific therapy of VZV-induced pain. We will test rdHSV expressing ligand-dependent glycine receptors for efficacy in blocking VZV induced pain signals in the rat following transcriptionally targeting of specific subpopulations of neurons. This will also reveal those neuron subtypes that transmit the VZV-induced pain signals. Together, these approaches have potential to revolutionize the way we think about how VZV induces pain and how we can more effectively provide relief to those unfortunate human patients suffering from PHN.

 描述（由适用提供）：疱疹后神经痛（PHN）是疱疹带状疱疹的常见，极其痛苦且令人衰弱的并发症，难以治疗，我对改善疗法的需求未被满足。当水痘病毒（VZV）从在水池期间在宿主感觉神经元中建立的潜在状态重新激活时，带状疱疹和PHN发生。全世界大多数成年人都有潜伏，PHN和疼痛的风险，发病率随着年龄的增长而增加，而我们的衰老社会则意味着带领和PHN可能会变得更加紧迫。 VZV导致持续性疼痛的机制尚不清楚。该项目针对FOA PA-13-118，扩展了与PHN相关的临床相关模型，其中VZV接种到大鼠FOODPAD中会诱导延长的机械性异差和热过敏。我们上覆的假设是，该模型将更好地理解VZV如何与神经系统相互作用以诱发疼痛，并成为测试改进的方法以治疗VZV引起的疼痛的平台。 AIM 1将定义VZV表达和大鼠复制的要求，以诱发疼痛。我们将检验以下假设：在没有生产性复制的情况下，有限的VZV表达足以驱动慢性疼痛指标。我们还将检验以下假设：缺乏诱发慢性疼痛的ORF47激酶不能引发疼痛所需的大鼠感染。第三，我们将通过 VZV IE62转录调节剂诱导与其他VZV蛋白无关的慢性疼痛行为。这些研究将确定VZV复制和表达的关键组成部分，以驱动模型中的疼痛状态。 AIM 2将重点关注感染神经元的作用 我们还将解决涉及驱动疼痛状态的神经元，该神经元是由特定的VZV疼痛诱导的蛋白质诱导的神经元直接驱动非副行为的蛋白质，从而利用了创新的配体依赖性的神经元特异性疼痛表达系统，该系统涉及甘氨酸受体的表达和由配体激活。我们还将解决涉及驱动疼痛状态的神经元亚型，该疼痛状态是由在复制缺陷HSV（RDHSV）载体中以神经元特异性启动子表达的特异性VZV疼痛诱导的蛋白质引起的。这也可以建立一个更延长的VZV诱导疼痛行为模型。 AIM 3将解决对VZV诱导的疼痛的改进和更具体的疗法。我们将测试表达配体依赖性甘氨酸受体的RDHSV，以在神经元的特定亚群体转录靶向后，以阻断大鼠VZV诱导的疼痛信号的效率。这还将揭示那些传递VZV诱导的疼痛信号的神经元亚型。这些方法共同考虑了我们思考VZV如何影响疼痛的方式，以及我们如何更有效地为那些不幸的人类患者提供PHN患者的方式。