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（由申请人提供）：带状疱疹后神经痛（PHN）是带状疱疹的一种常见、极度疼痛和使人衰弱的并发症，难以治疗，并且无法满足改善治疗的需求。水痘带状疱疹病毒（VZV）在水痘期间在宿主感觉神经元中建立的潜伏状态重新激活时发生带状疱疹和PHN。世界上大多数成年人都有患带状疱疹、PHN和疼痛的风险，这些风险可能非常严重，以至于严重降低生活质量。发病率随着年龄的增长而增加，我们的老龄化社会意味着带状疱疹和PHN可能成为更紧迫的公共卫生问题。VZV引起持续性疼痛的机制尚不清楚。该项目针对FOA PA-13-118，扩展了PHN的临床相关模型，其中VZV接种到大鼠足垫中诱导延长的机械异常性疼痛和热痛觉过敏。我们的假设是，该模型将提供更好的理解VZV如何与神经系统相互作用，以诱导疼痛，并成为一个平台，以测试VZV诱导的疼痛的治疗方法的改进。目的1明确VZV在大鼠体内表达和复制的条件，以诱导疼痛。我们将测试的假设，即有限的VZV表达是足以驱动慢性疼痛的指标，在没有生产性复制。我们还将检验缺乏ORF 47激酶的VZV不能引发疼痛所需的大鼠感染的假设，VZV不诱导慢性疼痛。第三，我们将通过以下方式解决固有属性： 其中VZV IE62转录调节因子诱导的慢性疼痛行为独立于其他VZV蛋白。这些研究将建立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将关注受感染神经元的作用 对疼痛状态的影响。我们将测试表达VZV蛋白的神经元直接驱动伤害反应行为的假设，利用创新的配体依赖性神经元特异性疼痛抑制系统，其涉及甘氨酸受体的表达和配体的激活。我们还将讨论参与驱动疼痛状态的神经元亚型，该疼痛状态由复制缺陷型HSV（rdHSV）载体中神经元特异性启动子表达的特异性VZV疼痛诱导蛋白诱导。这也可以建立一个更长的模型VZV诱导的疼痛行为。目标3将解决VZV引起的疼痛的改进和更特异性的治疗。我们将测试rdHSV表达配体依赖性甘氨酸受体在大鼠中阻断VZV诱导的疼痛信号的功效，随后转录靶向特定的神经元亚群。这也将揭示那些传递VZV诱导的疼痛信号的神经元亚型。总之，这些方法有可能彻底改变我们对VZV如何引起疼痛的思考方式，以及我们如何更有效地为那些不幸的PHN患者提供救济。