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: 10542746
• 负责人: RANDALL J. COHRS
• 金额: $ 43.75万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542746
• 关键词: Acceleration; 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; 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; In Vitro; Individual; Inflammation; Inflammatory; Inpatients; Interleukin-6; Interleukin-8; 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; System; 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; cerebral artery; cost; cytokine; histone modification; improved; in vitro Model; in vivo; inflammatory marker; inflammatory milieu; 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岁以上最常见的系统性脉管炎，临床表现为 症状和体征包括单侧头痛、颞动脉压痛、风湿性多肌痛、 疲劳、体重减轻和血清炎症标志物升高。诊断由TA活检证实 跨壁炎症、中层损害和巨细胞和/或上皮样细胞(GCA阳性)。皮质类固醇 治疗往往无效，患者会失明和中风。到2050年，预计将有182万人 老年人将患上GCA，其中36,500人将失去视力，这将导致美国的总预计成本 医疗体系838亿美元，其中65亿美元用于激素性骨折，11亿美元用于首次住院 GCA相关视力障碍的管理和7620万美元用于持续支持视力障碍的老年人 减损。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，其基础是：(1)相同 颅内VZV血管病变GCA阳性TA和脑动脉肉芽肿性炎症，(2) VZV抗原、DNA和疱疹病毒颗粒在高达70%的GCA阳性的TA和VZV感染的TA中存在 脑动脉，(3)最外层(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中的病毒沉积一致，(4) 类似的细胞因子(IL-6、IL-8和血管内皮生长因子)上调；(5)阿昔洛韦改善GCA。 然而，关键问题仍然存在：血管中的慢性促炎环境是如何维持的 血管壁，尤其是血管外膜成纤维细胞，有少量的VZV与炎症有关？我们的 初步数据显示VZV感染可诱导感染VZV的血管外膜产生促炎细胞因子 成纤维细胞和旁观者细胞在体外和体内以及血管外膜成纤维细胞之间的相似性 GCA和肺动脉高压构成了我们假设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 与致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验证这一假设 GCA外膜成纤维细胞炎性表型(Aim 1)和转录组(Aim 2)的分析 阳性和对照TA以确定VZV感染是否可以诱导这些基因表达的变化(AIMS 1 和2)。调节性组蛋白和炎性转录因子的表观遗传修饰 与宿主基因有关的促炎环境将被确定为提供一种机制 他们的慢性激活(目标3)。在成功完成这些目标后，我们的多学科团队将 应用先进技术提出新概念并开发新算法来管理大数据 SET显示血管外膜成纤维细胞可以经历表观遗传固定的表型变化 导致慢性炎症，这可能导致新的治疗方法来逆转导致的表观遗传修饰 在老年人群中感染VZV。