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
基本信息
- 批准号:9011769
- 负责人:
- 金额:$ 53.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Absence of pain sensationAddressAdultAffectAfferent NeuronsAgeAgingAnimal ModelAntiviral TherapyAutomobile DrivingBehaviorBiologyChickenpoxChronicComplicationComprehensionDataDevelopmentDiseaseElderlyEngineeringFundingGangliaGlycine ReceptorsGoalsHSV vectorHSV-1 vectorHealthHerpes zoster diseaseHerpesviridaeHerpesvirus Type 3HumanIncidenceInfectionLeadLigandsMediatingModelingNerveNervous system structureNeuronsPainPatientsPersistent painPhosphotransferasesPostherpetic neuralgiaPropertyProtein KinaseProteinsProteomePublic HealthQuality of lifeRattusReceptor ActivationRecombinantsReportingRepressionRiskRoleSignal TransductionSimplexvirusSocietiesSpecificitySystemTestingThermal HyperalgesiasTranscription CoactivatorTranscriptional ActivationViral AntigensViral ProteinsVirionVirus Replicationallodyniachronic painclinically relevantexperiencegenetic regulatory proteinimprovedindexinginnovationmechanical allodyniamutantpain behaviorpreventpromoterprotein expressionresponsetherapeutic genetreatment strategyvaricella-zoster virus immediate early protein 62vector control
项目摘要
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的、极其痛苦和使人衰弱的并发症,很难治疗,并且当水痘-带状疱疹病毒发生时,对改进的疗法的需求尚未得到满足。 (VZV) 从水痘期间宿主感觉神经元中建立的潜伏状态重新激活,全世界大多数成年人都面临带状疱疹、PHN 和疼痛的风险。随着年龄的增长,发病率可能会严重降低,而我们的老龄化社会意味着带状疱疹和带状疱疹病毒可能成为更加紧迫的公共卫生问题。针对 FOA PA-13-118,扩展了 PHN 的临床相关模型,其中将 VZV 接种到大鼠足垫中可诱导延长的机械异常性疼痛和热痛觉过敏。将更好地理解 VZV 如何与神经系统相互作用以诱发疼痛,并成为测试治疗 VZV 诱发疼痛的改进方法的平台。目标 1 将确定大鼠中 VZV 表达和复制诱发疼痛的要求。我们将检验以下假设:在缺乏有效复制的情况下,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 ORF47 激酶的 VZV(不会诱发慢性疼痛)不能引发大鼠感染。需要用于第三,我们将通过以下方式解决内在属性。
VZV IE62 转录调节因子独立于其他 VZV 蛋白诱导慢性疼痛行为。这些研究将确定 VZV 复制和表达在模型中驱动疼痛状态的关键成分。目标 2 将重点关注受感染神经元的作用。
我们将测试表达 VZV 蛋白的神经元直接驱动伤害行为的假设,利用一种创新的配体依赖性、神经元特异性疼痛抑制系统,该系统涉及甘氨酸受体的表达和配体的激活。参与驱动疼痛状态的神经元亚型是由复制缺陷型 HSV (rdHSV) 载体中神经元特异性启动子的特定 VZV 疼痛诱导表达蛋白诱导的。目标 3 将解决 VZV 诱导的疼痛的改进和更具体的治疗,我们将测试表达配体依赖性甘氨酸受体的 rdHSV 在转录靶向特定神经元亚群后阻断 VZV 诱导的疼痛信号的功效。这也将揭示那些传递 VZV 引起的疼痛信号的神经亚型,这些方法有可能彻底改变我们对 VZV 如何引起疼痛以及如何更有效地提供缓解的方式。致那些不幸患有 PHN 的人类患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Paul R. Kinchington其他文献
Paul R. Kinchington的其他文献
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{{ truncateString('Paul R. Kinchington', 18)}}的其他基金
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- 批准号:
10657725 - 财政年份:2022
- 资助金额:
$ 53.17万 - 项目类别:
Role of VZV Latency Transcript (VLT) and ORF63 in latency and reactivation
VZV 潜伏转录本 (VLT) 和 ORF63 在潜伏和重新激活中的作用
- 批准号:
10550430 - 财政年份:2020
- 资助金额:
$ 53.17万 - 项目类别:
Role of VZV Latency Transcript (VLT) and ORF63 in latency and reactivation
VZV 潜伏转录本 (VLT) 和 ORF63 在潜伏和重新激活中的作用
- 批准号:
10570901 - 财政年份:2020
- 资助金额:
$ 53.17万 - 项目类别:
Molecular studies of VZV infection, latency and reactivation in human neurons in-vitro
人类神经元水痘带状疱疹病毒感染、潜伏期和再激活的分子研究
- 批准号:
9052861 - 财政年份:2015
- 资助金额:
$ 53.17万 - 项目类别:
Molecular studies of VZV infection, latency and reactivation in human neurons in-vitro
人类神经元水痘带状疱疹病毒感染、潜伏期和再激活的分子研究
- 批准号:
9179591 - 财政年份:2015
- 资助金额:
$ 53.17万 - 项目类别:
Molecular studies of VZV infection, latency and reactivation in human neurons in-vitro
人类神经元水痘带状疱疹病毒感染、潜伏期和再激活的分子研究
- 批准号:
9052861 - 财政年份:2015
- 资助金额:
$ 53.17万 - 项目类别:
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8606907 - 财政年份:2013
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$ 53.17万 - 项目类别:
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:
7563123 - 财政年份:2009
- 资助金额:
$ 53.17万 - 项目类别:
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:
8410083 - 财政年份:2009
- 资助金额:
$ 53.17万 - 项目类别:
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