Prevention of VZV Reactivation

预防 VZV 重新激活

基本信息

批准号：
8476910
负责人：
RANDALL J. COHRS
金额：
$ 33.75万
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476910
关键词：
Acquired Immunodeficiency Syndrome Age American Antibodies Autonomic ganglion Autopsy Binding Binding Proteins Biological Assay Blindness Bovine Herpesvirus 2 Cellular Immunity Chickenpox Chickenpox Vaccine Childhood Chromatin Complex Cranial Nerves DNA DNA Sequence DNA-Binding Proteins Diagnosis Disease Elderly Epigenetic Process Equilibrium Equus caballus Euchromatin Event Exanthema Ganglia Gene Expression Profile 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 Neurologic Organ Transplantation Pain Paralysed Patients Post-Translational Protein Processing Postherpetic neuralgia Prevention Proteins Qualifying Regulation Rest Retinitis Spinal Ganglia Stroke Structure Suid Herpesvirus 1 Testing Therapeutic Agents Transcript Transcriptional Regulation Transplant Recipients Vaccines Vascular Diseases Viral Genes Virus Virus Diseases Virus Latency arm base chromatin immunoprecipitation chronic pain combat design experience histone modification latency associated transcript mutant nervous system disorder neurotropic physical separation prevent promoter protein complex public health relevance 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）：一种无处不在的神经性alphaherpesvirus（VZV），导致Varicella（chancerpox）在颅神经神经节，背部根神经节和沿整个神经Xis的自主神经节中变得潜在。 VZV重新激活，主要是在老年和免疫功能低下的个体中引起带状螺旋蛋白的重新激活，后来是带胸骨后神经痛，脊髓炎，脑膜脑炎，血管疾病和眼部疾病。没有其他人类疱疹病毒会引起如此广泛的疾病。尽管带状疫苗在免疫接种后的3年内将带状疱疹的发病率降低了51.3％，但每年仍有近40万美国人发展带状绿色，其中约200,000经验经验PHN；其他人则发展中风，瘫痪和失明。如果可以预防病毒重新激活，则不会发生这些神经系统疾病。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，在潜在感染的人类神经节中检测到不少于12个VZV转录本，而所有其他神经智Alphaherpesviruse（包括疱疹单纯疱疹1（HSV-1）（HSV-1）），转录单个潜伏期（LATCRIBSICE Transcript（LAT））。 HSV-1 LAT促进了病毒的重新激活，其启动子涂有含有增强转录后翻译后修饰的组蛋白。其他HSV-1基因的启动子受抑制转录（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子对组蛋白复合物的物理分离。总体而言，HSV-1 LAT促进潜在病毒DNA重新激活的能力为我的假设提供了一种理由：我的假设是，在潜在感染的人为神经节中转录的一个或多个VZV基因通过对组蛋白修饰的作用促进潜在的VZV促进潜在的VZV。两个具体的目标将检验我们的假设。 AIM 1将识别组蛋白在潜伏期表达的VZV基因启动子上的翻译后修饰。 AIM 2将研究维持正式和异型组蛋白修饰的机制。我们具有独特的资格进行拟议的研究，因为我们在尸检时持续不断供应新鲜的人神经节，数十年来研究潜在和裂解的VZV转录组，并且已经开发了基于芯片的测定和基于PCR的多路复用测定法，以分析人类神经神经神经神经节的潜在感染了VZV。凭借对VZV基因的表观遗传调节的理解，我们将能够设计治疗剂来对抗病毒重新激活并减轻老年人的神经系统疾病。