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: 9491548
• 负责人: RANDALL J. COHRS
• 金额: $ 45.02万
• 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/9491548
• 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; Data Set; 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; Immune; 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; multidisciplinary; novel therapeutics; particle; prevent; programs; pulmonary arterial hypertension; transcription factor; transcriptome; transcriptome sequencing; 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 岁以上个体中最常见的系统性血管炎，表现为 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。 TA 活检证实诊断 透壁炎症、内侧损伤和巨细胞和/或上皮样细胞（GCA 阳性）。皮质类固醇 治疗常常无效，患者会失明和中风。到 2050 年，预计将有 182 万 老年人将患上 GCA，其中 36,500 人将失去视力，从而给美国带来预计总成本 医疗系统耗资 838 亿美元，其中 65 亿美元用于类固醇引起的骨折，11 亿美元用于初始住院患者 管理与 GCA 相关的视力障碍，以及 7,620 万美元用于持续支持视力障碍老年人 损害。我们已经证明 GCA 是水痘带状疱疹病毒 (VZV) 血管病的一种形式，基于：(1) 相同 GCA 阳性 TA 和颅内 VZV 血管病变脑动脉的肉芽肿性炎症，(2) 高达 70% GCA 阳性 TA 和 VZV 感染者中存在 VZV 抗原、DNA 和疱疹病毒颗粒 脑动脉，(3) 最外动脉层（外膜）作为初始炎症部位的重要性 和 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，以及 (5) 使用阿昔洛韦治疗改善 GCA。 然而，关键问题仍然存在：血管中如何维持慢性促炎环境 血管壁，尤其是血管外膜成纤维细胞，与少量VZV是否有炎症相关？我们的 初步数据显示，VZV 感染可在 VZV 感染的血管外膜中诱导促炎细胞因子 体外和体内的成纤维细胞和旁观者细胞，以及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的基础，即 VZV 感染血管 外膜成纤维细胞通过启动表观遗传重编程来促进 GCA，从而导致持续的 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个假设 分析 GCA- 外膜成纤维细胞的炎症表型（目标 1）和转录组（目标 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（目标 1 和2）。调节组蛋白的表观遗传修饰与炎症转录因子相关 将确定负责促炎环境的宿主基因，以提供一种机制 它们的慢性激活（目标 3）。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 表明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，从而可以产生新的疗法来逆转导致的表观遗传修饰 老年人群中水痘带状疱疹病毒 (VZV) 感染。