Investigating the VZV-induced epigenetic modifications of vascular adventitial fibroblasts that contribute to persistent inflammation and VZV vasculopathy

研究 VZV 诱导的血管外膜成纤维细胞表观遗传修饰导致持续炎症和 VZV 血管病变

• 批准号: 10097966
• 负责人: RANDALL J. COHRS
• 金额: $ 45.18万
• 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/10097966
• 关键词: Accounting; Acyclovir; Adrenal Cortex Hormones; Affect; Age-Years; Algorithms; Arteries; Autopsy; Biopsy; Blindness; Blood Vessels; Body Weight decreased; Brain; Cadaver; Cells; ChIP-seq; Chronic; Clinics and Hospitals; Complex; DNA; Data; Data Analyses; Deposition; Diagnosis; Disease; Disease Progression; Elderly; Ensure; Environment; Environmental Risk Factor; Epigenetic Process; Epithelioid Cells; Fatigue; Fibroblasts; Fracture; Gene Expression; Genes; Genetic Transcription; Genome; Giant Cells; Granulomatous; Health system; Herpesviridae; Herpesvirus Type 3; Histone Deacetylase Inhibitor; Histones; Human; Hypoxia; IL8 gene; In Vitro; Individual; Inflammation; Inflammatory; Inpatients; Interleukin-6; Interleukins; Lead; Link; Lung; Medial; Modification; Nerve Fibers; Onset of illness; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Phenotype; Play; Polymyalgia Rheumatica; Population; Production; Role; Serum; Signs and Symptoms; Site; Steroids; Stroke; Technology; Temporal Arteries; Temporal Arteritis; Testing; Tunica Adventitia; Unilateral Headaches; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular remodeling; Vasculitis; Viral Antigens; Virus; Virus Diseases; Vision; Visual impairment; base; cerebral artery; cost; cytokine; histone modification; in vitro Model; in vivo; inflammatory marker; intracranial artery; large datasets; multidisciplinary; novel therapeutics; particle; prevent; programs; pulmonary arterial hypertension; transcription factor; transcriptome; transcriptome sequencing; tumor-immune system interactions; varicella zoster virus vasculopathy; vascular inflammation

Giant cell arteritis (GCA), the most common systemic vasculitis in individuals >50 years of age, presents with symptoms and signs including unilateral headache, temporal artery (TA) tenderness, polymyalgia rheumatica, fatigue, weight loss and elevated serum inflammatory markers. Diagnosis is confirmed by TA biopsy showing transmural inflammation, medial damage and giant and/or epithelioid cells (GCA-positive). Corticosteroid treatment is often ineffective and patients develop blindness and stroke. By 2050, a predicted 1.82 million elderly individuals will develop GCA, of which 36,500 will lose vision resulting total projected cost to the USA health system of $83.8 billion with $6.5 billion for steroid-induced fracture, $1.1 billion for initial inpatient management of GCA-associated visual impairment and $76.2 million for ongoing support of elderly with visual impairment. We have shown GCA is a form of varicella zoster virus (VZV) vasculopathy based on: (1) identical granulomatous inflammation in GCA-positive TAs and cerebral arteries of intracranial VZV vasculopathy, (2) presence of VZV antigen, DNA and herpesvirus particles in up to 70% GCA-positive TAs and in VZV-infected cerebral arteries, (3) importance of the outermost arterial layer (adventitia) as the site of initial inflammation and VZV infection consistent with virus deposition from nerve fibers that terminate in adventitia, (4) upregulation of similar cytokines (IL-6, IL-8 and VEGF), and (5) improvement of GCA with acyclovir treatment. However, the critical question remains: how is a chronic proinflammatory environment maintained in the vessel wall, especially in vascular adventitial fibroblasts, with a small amount of VZV relative to inflammation? Our preliminary data showing VZV infection induces proinflammatory cytokines in VZV-infected vascular adventitial fibroblasts and bystander cells in vitro and in vivo, along with the similarities between adventitial fibroblasts in GCA and pulmonary arterial hypertension forms the basis of our hypothesis that VZV infection of vascular adventitial fibroblasts contributes to GCA by initiating epigenetic reprogramming resulting in continued transcription of host genes associated with proinflammatory cytokine production. We will test this hypothesis by profiling the inflammatory phenotype (Aim 1) and transcriptome (Aim 2) of adventitial fibroblasts from GCA- positive and control TAs to determine if VZV infection can induce these changes in gene expression (Aims 1 and 2). The epigenetic modification of regulatory histones and inflammatory transcription factors associated with host genes accounting for the proinflammatory environment will be determined to provide a mechanism for their chronic activation (Aim 3). Upon successful completion of these aims, our multi-disciplinary team will present a new concept by applying advanced technology and develop new algorithms to manage large data sets to show that vascular adventitial fibroblasts can undergo an epigenetically fixed phenotypic change resulting in chronic inflammation that can lead to new therapies to reverse epigenetic modifications that result from VZV infection in the elderly population.

巨细胞动脉炎（GCA）是50岁以上人群中最常见的系统性血管炎， 症状和体征包括单侧头痛、颞动脉（TA）压痛、风湿性多肌痛， 疲劳、体重减轻和血清炎症标志物升高。通过TA活检证实诊断， 透壁性炎症、中膜损伤和巨细胞和/或上皮样细胞（GCA阳性）。皮质类固醇 治疗往往无效，病人会失明和中风。到2050年，预计将有182万人 老年人将发展GCA，其中36，500人将失去视力，导致美国的总预计成本 卫生系统838亿美元，其中65亿美元用于类固醇引起骨折，11亿美元用于初次住院 管理与GCA相关的视力障碍，并为视力障碍的老年人提供7620万美元的持续支持 损伤我们已经证明GCA是水痘带状疱疹病毒（VZV）血管病变的一种形式，基于：（1）相同的 GCA阳性TA和颅内VZV血管病变脑动脉中的肉芽肿性炎症，（2） 在高达70%的GCA阳性TA和VZV感染的TA中存在VZV抗原、DNA和疱疹病毒颗粒 脑动脉，（3）最外层动脉（外膜）作为初始炎症部位的重要性 VZV感染与终止于外膜的神经纤维的病毒沉积一致，（4） 类似细胞因子（IL-6、IL-8和VEGF）的上调，和（5）用阿昔洛韦治疗改善GCA。 然而，关键问题仍然存在：慢性促炎环境是如何在血管中维持的 血管壁，特别是血管外膜成纤维细胞，与少量的VZV相对于炎症？我们 显示VZV感染诱导VZV感染的血管外膜中促炎细胞因子的初步数据 成纤维细胞和旁观者细胞在体外和体内，沿着与外膜成纤维细胞之间的相似性， GCA和肺动脉高压形成了我们假设VZV感染血管的基础， 外膜成纤维细胞通过启动表观遗传重编程而促进GCA， 与促炎细胞因子产生相关的宿主基因的转录。我们将通过以下方式检验这一假设： 分析来自GCA的外膜成纤维细胞的炎性表型（Aim 1）和转录组（Aim 2）， 阳性和对照TA，以确定VZV感染是否可以诱导基因表达的这些变化（目的1 和2）。调节性组蛋白和炎症转录因子的表观遗传修饰 与宿主基因占促炎环境将被确定为提供一种机制， 3、慢性炎症（Aim 3）。在成功完成这些目标后，我们的跨专业团队将 通过应用先进的技术提出新的概念，并开发新的算法来管理大数据 表明血管外膜成纤维细胞可以经历表观遗传学固定的表型变化， 导致慢性炎症，这可能导致新的疗法来逆转表观遗传修饰， VZV在老年人群中的感染。