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 ~ 50岁人群中最常见的全身性血管炎