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
• 负责人: Paul R. Kinchington
• 金额: $ 1.36万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848656
• 关键词: Address; Afferent Neurons; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antiviral Agents; Attenuated; Bacterial Artificial Chromosomes; Behavioral; Biology; Chickenpox; Complication; DNA; Development; Disease; Elderly; Enkephalins; Foundations; Future; Ganglia; Gene Expression; Gene Transduction Agent; Generations; Genetic; Glutamate Decarboxylase; Glycine Receptors; HSV vector; Herpes zoster disease; Herpesviridae; Herpesvirus Type 3; Human; Hyperalgesia; Hypersensitivity; Incidence; Individual; Infection; Inflammation; Inflammation Mediators; Injection of therapeutic agent; Interleukin-4; Knowledge; Lead; Life; Lytic Phase; Mediating; Methods; Modeling; Modification; Molecular; Molecular Target; Myxoid cyst; Nature; Nerve; Neurons; Neuropathy; Nociception; Nociceptors; Pain; Pain Measurement; Patients; Pattern; Persistent pain; Postherpetic neuralgia; Process; Protein Kinase; Proteins; Public Health; Quality of life; Rattus; Recombinants; Recovery; Refractory; Regulator Genes; Signal Transduction; Simplexvirus; Societies; Spinal Cord; Spinal Ganglia; Spinal cord posterior horn; Staging; System; TNFR-Fc fusion protein; Testing; Therapeutic; Therapeutic Intervention; Thermal Hyperalgesias; Up-Regulation; Vaccines; Viral; Viral Antigens; Viral Genes; Viral Proteins; Virus Diseases; Virus Latency; Work; allodynia; animal pain; base; clinically relevant; gene therapy; genetic regulatory protein; human disease; improved; indexing; inflammatory neuropathic pain; inflammatory pain; interdisciplinary approach; mechanical allodynia; mutant; novel; novel strategies; pathogen; prevent; proenkephalin; protein expression; response; vaccine candidate; vector; viral DNA; virology

DESCRIPTION (provided by applicant): Post-Herpetic Neuralgia (PHN) is a common and exceedingly painful complication of herpes zoster that is debilitating, intractable, long-lasting and difficult to treat. PHN increases dramatically with age, and is thus a disease of the elderly which may profoundly reduce the quality of life. Given the aging nature of our society, PHN will become an even more pressing public health concern. Zoster and PHN occur when the human herpesvirus, varicella-zoster virus (VZV), reactivates from a latent state that was established in the host sensory neurons during chickenpox. While viral replication induces nerve damage and inflammation to initiate pain, the mechanisms by which VZV causes persistent pain are not well understood. This project is directed to FOA PA-07-282, and will center on a new clinically relevant model of VZV-induced pain in which prolonged hyperalgesia and allodynia occur following injection of human VZV into the rat hindpaw. The overlying hypothesis of this proposal is that by using this new rat model we will be able to better comprehend how VZV interacts with the primary afferent system to induce pain and test novel gene therapy approaches to treat VZV induced pain. In Specific Aim 1, we will examine the biology of VZV infection in the rat by characterizing viral and pain marker protein expression in the dorsal root ganglion (DRG) sensory neurons before, during and after VZV-induced nociception, using a comprehensive panel of antibodies. We will determine which VZV proteins are expressed in the DRG at each stage and address if viral gene expression patterns correlate with the pain response and recovery from it. We will also identify types of neurons expressing VZV antigens and determine if they display an upregulation of markers of neuropathic and/or inflammatory pain at both the DRG and the spinal cord. This work will establish the underlying VZV biology in the model and whether the pain response is a result of an infectious process with similarities to human VZV lytic infections or to VZV latency. In Specific aim 2, we will ask what specific VZV proteins are necessary to induce pain by testing the ability of: 1) various mutant VZV recombinants, each altered in a specific regulatory viral gene, and 2) various HSV vectors, each constructed to express a single VZV regulatory gene, to induce nociception. This may identify specific VZV proteins for further targeting in developing anti-pain strategies, and may lead to improved vaccines without the ability to induce PHN. The third specific aim will explore new avenues of treatment by testing the hypothesis that HSV vector-mediated delivery of modulators of pain can reduce the allodyna and hyperalgesia induced by VZV. We will investigate the use of HSV vectors expressing pro-enkephalin, GAD, the glycine receptor, and anti inflammatory proteins to treat VZV-induced hypersensitivity in the model, all of which have been shown to reduce pain in other systems. Together, exploration of this model may lead to an understanding of cellular changes that may underlie the generation of pain by VZV that will not only add to knowledge of pathogen:host interactions in VZV infection, but may help in developing new molecular targets for therapeutic intervention. This project studies a new model of pain induced by the herpesvirus varicella zoster virus that is reflective of a common and highly debilitating human disease of the elderly, post herpetic neuralgia (PHN). The examination of the model may identify new targets for the development of anti-pain strategies, and may lead to the identification of improved vaccine candidates that are unable to induce pain. The project may also identify new methods to alleviate PHN using gene therapy approaches.

描述（由申请人提供）：疱疹后神经痛（PHN）是疱疹带状疱疹的常见且极其痛苦的并发症，它使人衰弱，顽固，持久，持久且难以治疗。 PHN随着年龄的增长而大大增加，因此是老年人的一种疾病，可以极大地降低生活质量。鉴于我们社会的衰老本质，PHN将成为更加紧迫的公共健康问题。当人类疱疹病毒，水痘带状疱疹病毒（VZV）从宿主感觉神经元在水痘期间建立的潜在状态重新激活时，带状疱疹和PHN发生。虽然病毒复制会引起神经损伤和炎症引发疼痛，但VZV引起持续性疼痛的机制尚不清楚。该项目针对FOA PA-07-282，将以新的临床相关模型的VZV诱导疼痛模型为中心，在该模型中，在将人VZV注射到大鼠印度河中后，长时间的痛觉过敏和异常性症。该提议的上覆的假设是，通过使用这种新的大鼠模型，我们将能够更好地理解VZV如何与主要传入系统相互作用，以诱发疼痛并测试新型基因治疗方法来治疗VZV诱导的疼痛。在特定的目标1中，我们将通过表征在VZV引起的后，中和之后，使用全面的抗体面板来检查大鼠中VZV感染的生物学。 。我们将确定在每个阶段的DRG中表达哪些VZV蛋白，并解决病毒基因表达模式是否与疼痛反应及其恢复相关。我们还将确定表达VZV抗原的神经元的类型，并确定它们是否在DRG和脊髓上都表现出神经性疼痛和/或炎症性疼痛的上调。这项工作将在模型中建立潜在的VZV生物学，以及疼痛反应是与人类VZV裂解感染相似还是与VZV潜伏期相似的传染过程的结果。在特定的目标2中，我们将询问哪些特定的VZV蛋白通过测试以下能力来诱导疼痛是什么必要的：1）各种突变体VZV重组因素，每种都在特定的调节病毒基因中改变，而2）各种HSV载体，每种都构建以表达以表达表达单个VZV调节基因，以诱导伤害感受。这可能会确定特定的VZV蛋白，以进一步靶向开发抗pain策略，并可能导致疫苗的改善而无需诱导PHN的能力。第三个具体目的将通过测试HSV载体介导的疼痛调节剂传递的假设可以减少VZV引起的同andyna和痛觉过敏的假设来探索新的治疗途径。我们将研究表达前脑蛋白酶，GAD，甘氨酸受体和抗炎性蛋白来处理模型中VZV诱导的超敏反应的HSV载体的使用，所有这些都显示出其他系统中的疼痛。总之，对该模型的探索可能会导致对细胞变化的理解，这可能是VZV产生疼痛的基础，这不仅会增加病原体的知识：VZV感染中的宿主相互作用，而且可能有助于开发用于治疗干预的新分子靶标。该项目研究了由疱疹病毒素系带状疱疹病毒引起的一种新的疼痛模型，该模型反映了老年人的常见且高度令人衰弱的人类疾病，后疱疹神经痛（PHN）。对模型的检查可能会确定针对反苦伙伴策略发展的新目标，并可能导致鉴定无法诱发疼痛的疫苗候选者的改善。该项目还可以使用基因疗法方法来确定减轻PHN的新方法。