Prevention of VZV Reactivation

预防 VZV 重新激活

基本信息

批准号：
9208821
负责人：
RANDALL J. COHRS
金额：
$ 34.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-15 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9208821
关键词：
Acquired Immunodeficiency Syndrome Age American Antibodies Autonomic ganglion Autopsy Binding Binding Proteins Biological Assay Blindness Cattle Cellular Immunity Chickenpox Chickenpox Vaccine Childhood Chromatin Complex Cranial Nerves DNA DNA Sequence DNA-Binding Proteins Diagnosis Disease Elderly Equilibrium Equus caballus Euchromatin Event Exanthema Ganglia Genes Genetic Transcription Genome Health Herpes Simplex Infections Herpes zoster disease Herpesviridae Herpesvirus 1 Herpesvirus Type 3 Heterochromatin Histones Human Immunization Immunocompromised Host Immunosuppression Incidence Incontinence Individual Latent Virus Life Location Lytic Malignant Neoplasms Meningoencephalitis Modification Molecular Mus Myelitis Neuralgia Neuraxis Organ Transplantation Pain Paralysed Patients Post-Translational Protein Processing Postherpetic neuralgia Prevention Proteins Rest Retinitis Spinal Ganglia Stroke Structure Testing Therapeutic Agents Transcript Transcriptional Regulation Transplant Recipients Vascular Diseases Viral Genes Viral Genome Virus Virus Diseases Virus Latency Zoster Vaccine base chromatin immunoprecipitation chronic pain combat design epigenetic regulation experience histone modification latency associated transcript mad itch virus mutant nervous system disorder neurotropic physical separation prevent promoter protein complex public health relevance reactivation from latency transcriptome varicella zoster virus vasculopathy viral DNA

项目摘要

DESCRIPTION (provided by applicant): Varicella zoster virus (VZV), a ubiquitous neurotropic alphaherpesvirus that causes varicella (chickenpox), becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. VZV reactivation, mostly in elderly and immunocompromised individuals, causes zoster, often followed by postherpetic neuralgia, myelitis, meningoencephalitis, vasculopathy and ocular diseases. No other human herpesvirus causes such a wide spectrum of disease. Although zoster vaccine reduces the incidence of zoster by 51.3% within 3 years after immunization, nearly 400,000 Americans still develop zoster every year, of which about 200,000 experience PHN; others develop stroke, paralysis and blindness. None of these neurological disorders would occur if virus reactivation could be prevented. Although the molecular mechanism(s) of VZV reactivation is unknown, VZV is unique in that no less than 12 VZV transcripts are detected in latently infected human ganglia, whereas all other neurotropic alphaherpesviruses, including herpes simplex-1 (HSV-1), transcribe a single latency associated transcript (LAT). HSV-1 LAT facilitates virus reactivation, and its promoter is coated with histones containing post-translational modifications that enhance transcription (euchromatin). Promoters for other HSV-1 genes are bound by modified histones that repress transcription (heterochromatin). The mechanism by which histone modifications are maintained is unknown, but may involve physical separation of histone complexes by chromatin insulators. Overall, the ability of the HSV-1 LAT to facilitate reactivation of latent virus DNA provides a rationale for my hypothesis that one or more VZV genes transcribed in latently infected human ganglia facilitate reactivation of latent VZV through their effects on histone modification. Two specific aims will test our hypothesis. Aim 1 will identify post- translational modifications of histones on promoters of VZV genes expressed during latency. Aim 2 will investigate the mechanism by which euchromatic and heterochromatic histone modification are maintained. We are uniquely qualified to conduct our proposed studies since we have a continuous supply of fresh human ganglia obtained at autopsy, decades of expertise studying both the latent and lytic VZV transcriptome, and have developed ChIP assays and PCR-based multiplex assays to analyze human ganglia latently infected with VZV. Armed with an understanding of the epigenetic regulation of VZV genes, we will be able to design therapeutic agents to combat virus reactivation and mitigate sever neurologic disease in the elderly.

描述（由申请人提供）：水痘带状疱疹病毒（VZV）是一种普遍存在的嗜神经性α疱疹病毒，可引起水痘（水痘），潜伏在整个神经轴的颅神经节、背根神经节和自主神经节中。 VZV 重新激活主要发生在老年人和免疫功能低下的个体中，会导致带状疱疹，随后通常会出现带状疱疹后神经痛、脊髓炎、脑膜脑炎、血管病变和眼部疾病。没有其他人类疱疹病毒能引起如此广泛的疾病。尽管带状疱疹疫苗在免疫后3年内可将带状疱疹发病率降低51.3%，但每年仍有近40万美国人患上带状疱疹，其中约20万患有PHN；其他人则出现中风、瘫痪和失明。如果可以防止病毒重新激活，这些神经系统疾病就不会发生。尽管 VZV 重新激活的分子机制尚不清楚，但 VZV 的独特之处在于，在潜伏感染的人类神经节中检测到不少于 12 个 VZV 转录本，而所有其他嗜神经性 α 疱疹病毒，包括单纯疱疹-1 (HSV-1) 都转录单个潜伏期相关转录本 (LAT)。 HSV-1 LAT 促进病毒重新激活，其启动子涂有组蛋白，这些组蛋白含有增强转录的翻译后修饰（常染色质）。其他 HSV-1 基因的启动子与抑制转录（异染色质）的修饰组蛋白结合。维持组蛋白修饰的机制尚不清楚，但可能涉及染色质绝缘体对组蛋白复合物的物理分离。总体而言，HSV-1 LAT 促进潜伏病毒 DNA 重新激活的能力为我的假设提供了理论依据，即在潜伏感染的人类神经节中转录的一个或多个 VZV 基因通过其对组蛋白修饰的影响来促进潜伏 VZV 的重新激活。两个具体目标将检验我们的假设。目标 1 将鉴定潜伏期间表达的 VZV 基因启动子上组蛋白的翻译后修饰。目标 2 将研究维持常染色质和异染色质组蛋白修饰的机制。我们拥有独特的资格来开展我们提出的研究，因为我们拥有尸检中获得的新鲜人类神经节的持续供应，数十年研究潜伏和裂解 VZV 转录组的专业知识，并开发了 ChIP 测定和基于 PCR 的多重测定来分析人类神经节潜伏感染水痘带状疱疹病毒。了解了 VZV 基因的表观遗传调控后，我们将能够设计出治疗药物来对抗病毒重新激活并减轻老年人的严重神经系统疾病。