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），这是个体中最常见的全身血管炎，> 50岁，呈现为 症状和体征，包括单侧头痛，颞动脉（TA）压痛，多肌痛性风湿病， 疲劳，体重减轻和血清炎症标记升高。通过显示的TA活检证实诊断 透壁炎症，内侧损伤以及巨大和/或上皮细胞（GCA阳性）。皮质类固醇 治疗通常是无效的，患者患有失明和中风。到2050年，一个预计182万 老年人将发展GCA，其中36,500人将失去视力，从而导致美国的总预期成本 卫生系统为838亿美元，类固醇引起的骨折为65亿美元，初始住院期11亿美元 与GCA相关的视觉障碍的管理和7620万美元，以持续支持老年人 损害。我们已经显示GCA是一种基于以下方面的Vericella带状疱疹病毒（VZV）血管病的一种形式。（1）相同 颅内VZV血管病的GCA阳性TA和脑动脉中的肉芽肿性炎症，（2） VZV抗原，DNA和疱疹病毒颗粒的存在高达70％GCA阳性TA，并在VZV感染中 脑动脉，（3）最外层动脉层（床）作为初始炎症部位的重要性 和VZV感染与终止中质神经纤维的病毒沉积一致，（4） 类似的细胞因子（IL-6，IL-8和VEGF）的上调，以及（5）通过Acyclovir治疗改善GCA。 但是，关键的问题仍然存在：如何在血管中维持慢性促炎环境 壁，尤其是在血管外膜成纤维细胞中，相对于炎症而言少量VZV？我们的 初步数据显示VZV感染在VZV感染的血管外膜中诱导促炎性细胞因子 成纤维细胞和体外的成纤维细胞和体内的旁观细胞，以及外在成纤维细胞之间的相似之处 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而导致GCA，导致持续 与促炎细胞因子产生相关的宿主基因的转录。我们将通过 分析GCA-的炎症表型（AIM 1）和转录组（AIM 2） 阳性和控制TA以确定VZV感染是否会诱导基因表达的这些变化（目标1 和2）。调节性组蛋白和炎症转录因子的表观遗传修饰 随着宿主基因的核算环境，将确定为提供一种机制 他们的慢性激活（AIM 3）。成功完成这些目标后，我们的多学科团队将 通过应用先进技术并开发新算法来管理大型数据，提出一个新概念 设置表明血管外膜成纤维细胞可以发生表观遗传固定的表型变化 导致慢性炎症，可能导致新的疗法逆转表观遗传修饰，从而导致 来自老年人群的VZV感染。