A major contributor of serious multisystem disease in the elderly: varicella zoster virus-induced inflammation

老年人严重多系统疾病的主要原因：水痘带状疱疹病毒引起的炎症

• 批准号: 9491544
• 负责人: Maria Acena Nagel
• 金额: $ 236.43万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9491544
• 关键词: Administrator; Adrenal Glands; Affect; Age; Age-Years; Aging; American; Aorta; Aortitis; Autopsy; Bioinformatics; Biological Assay; Biological Markers; Biology; Biometry; Biopsy; Bladder Dysfunction; Blindness; Blood Vessels; Burning Mouth Syndrome; Businesses; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Characteristics; Chickenpox; Chronic; Clinical; Clinics and Hospitals; Collaborations; Dementia; Disease; Elderly; Ensure; Environment; Epigenetic Process; Evolution; Exanthema; Expression Profiling; Facial Pain; Fibroblasts; Flow Cytometry; Formalin; Ganglia; Gastric ulcer; Genetic Transcription; Goals; Granulomatous; Headache; Hepatitis; Herpes zoster disease; Herpesvirus Type 3; Histone Deacetylase Inhibitor; Human; Immune; Immune system; Immunohistochemistry; Immunology; Incidence; Inflammation; Inflammatory; Inflammatory Response; Intestines; Ipsilateral; Measures; Modeling; Morbidity - disease rate; Myocardial Infarction; Nerve Fibers; Neuraxis; Neurology; Neurons; Ophthalmology; Organ; Pain; Pancreatitis; Paraffin Embedding; Pathway interactions; Patients; Phenotype; Postherpetic neuralgia; Postmenopause; Primary Infection; Primates; Protocols documentation; Reagent; Research; Role; Scientist; Site; Skin; Specificity; Stroke; Structure; Structure of trigeminal ganglion; Suicide; T-Lymphocyte; Temporal Arteries; Temporal Arteritis; Testing; Time; Tissue Banks; Tissues; Vaccines; Vasculitis; Viral; Viral Antigens; Virus; Virus Diseases; Woman; Zoster Vaccine; aging population; body system; cerebral artery; chromatin immunoprecipitation; chromatin modification; chronic pain; clinically relevant; cohesion; cytokine; experience; human old age (65+); intracranial artery; macrophage; mortality; multidisciplinary; new therapeutic target; novel; organizational structure; prevent; programs; statistics; success; transcriptome; transcriptome sequencing; uptake; varicella zoster virus vasculopathy; vascular inflammation; virology

The goal of this Program Project is to prevent disease in the elderly upon reactivation of varicella zoster virus (VZV), the most common virological cause of disease associated with aging. By 2050, >83 million Americans will be over 65 years old with 95% harboring latent VZV. As the immune system ages, VZV will reactivate in >50% to produce zoster (shingles) complicated by postherpetic neuralgia, as well as serious multisystem disorders with or without rash including dementia, stroke, giant cell arteritis, vision loss, burning mouth syndrome, myocardial infarction, and bowel and bladder dysfunction. While zoster vaccine reduces the incidence of zoster and PHN, it has not been shown to be protective in other VZV-associated diseases. The characteristic theme in these diseases is persistent, VZV-induced inflammation that results in tissue damage. Thus, this Program Project, composed of 3 Projects and 2 Cores (Administrative and Scientific) will: determine the role of VZV in persistent vascular inflammation that characterizes giant cell arteritis (GCA), the most common systemic vasculitis in elderly that causes headaches, stroke and blindness; examine epigenetic changes in vascular adventitial fibroblasts in GCA that contribute to a persistent proinflammatory phenotype; and trace the evolution of virus infection and inflammation in multiple clinically relevant tissues up to 6 months post-zoster in a simian model of varicella virus reactivation. Project 1 will determine the proinflammatory environment and identify biomarkers in formalin-fixed, paraffin- embedded temporal arteries from GCA patients (GCA-positive TAs) using a novel, validated RNA sequencing strategy that provides complete cellular and viral transcriptome expression profiles. This Project will also determine VZV antigen specificity of T cells isolated from GCA-positive TAs acquired immediately at biopsy. Project 2 tests the hypothesis that adventitial fibroblasts isolated from GCA-positive TAs undergo epigenetic reprogramming such that they are proinflammatory, raising the possibility of treatment with histone deacetylase inhibitors. Project 3 uses a primate model to determine critical virus-host immune cell interactions within multiple tissues at multiple times post-zoster, a study which is otherwise impossible to conduct in humans since VZV-infected tissue at defined times post-zoster is not available. The success of this Program Project is ensured by: 1) collaborations among clinicians and scientists with expertise in VZV biology, immunology, epigenetics, bioinformatics, biostatistics and ophthalmology; 2) prior establishment of proposed protocols; and 3) availability of fresh TA biopsies from multiple hospitals/clinics in the Rocky Mountain Region and access to primate tissues through collaborations with Tulane National Primate Research Center. Together, the studies hold great translational promise since they will provide valuable information about the mechanisms leading to persistent VZV-induced inflammation and tissue damage, thereby providing new therapeutic targets to reduce/prevent clinical disease predominantly affecting the vulnerable aging population.

该计划项目的目的是防止毒all虫复活后老年人的疾病 病毒（VZV），这是与衰老相关的最常见病毒学原因。到2050年，> 8300万 美国人将超过65岁，有95％的潜在VZV。随着免疫系统的年龄，VZV将会 重新激活> 50％以产生带胸神经痛复杂的带状带（带状疱疹），并且严重 多或没有皮疹的多系统疾病，包括痴呆，中风，巨细胞动脉炎，视力丧失，燃烧 口腔综合征，心肌梗塞以及肠和膀胱功能障碍。系带疫苗减少 带状疱疹和PHN的发病率尚未证明在其他VZV相关疾病中具有保护性。这 这些疾病中的特征主题是持续的，VZV引起的炎症，导致组织 损害。因此，该计划项目由3个项目和2个核心（行政和科学）组成： 确定VZV在持续性血管炎症中的作用，表征了巨细胞动脉炎 （GCA）是老年人最常见的全身性血管炎，导致头痛，中风和失明； 检查GCA中血管外膜成纤维细胞的表观遗传变化，这有助于持续 促炎表型；并追踪多个病毒感染和炎症的演变 临床相关的组织在猿猴病毒重新激活的猿猴模型中长达6个月。 项目1将确定促炎环境，并确定福尔马林固定的石蜡中的生物标志物 使用新型的，经过验证的RNA测序的GCA患者（GCA阳性TAS）的嵌入式颞动脉 提供完整的细胞和病毒转录组表达谱的策略。这个项目也将 确定从活检中立即获得的GCA阳性TA分离的T细胞的VZV抗原特异性。 项目2检验了以下假设：从GCA阳性TA中分离出的外在成纤维细胞经历表观遗传学 重新编程使它们具有促炎性，从而增加了用组蛋白脱乙酰基酶治疗的可能性 抑制剂。项目3使用灵长类动物模型来确定关键的病毒宿主免疫细胞相互作用 神秘后多次多次多次组织，这项研究否则在人类中不可能进行 由于在定义的时期内的vzv感染的组织没有可用。该计划项目的成功是 确保：1）临床医生和科学家之间具有VZV生物学，免疫学专业知识的科学家， 表观遗传学，生物信息学，生物统计学和眼科； 2）事先制定拟议的协议；和 3）从落基山地区的多家医院/诊所提供新鲜的TA活检并进入 灵长类动物组织通过与图兰国家灵长类动物研究中心合作。一起研究 持有巨大的翻译承诺，因为他们将提供有关导致机制的宝贵信息 持续的VZV引起的炎症和组织损伤，从而为 减少/预防临床疾病主要影响脆弱的老龄化人群。