Role of EBV gene products in lung fibrogenesis

EBV基因产物在肺纤维化中的作用

基本信息

批准号：
7231031
负责人：
Joseph A Lasky
金额：
$ 36.17万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-08 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7231031
关键词：
Address Alveolar Alveolus Animal Model Apoptosis Appearance Area Automobile Driving BZLF1 protein, Herpesvirus 4, Human Bacteriology Binding Biology Bleomycin Cell Line Cell Survival Cell surface Cells Chronic lung disease Clinical Collaborations Communicable Diseases Cultured Cells Data Development Disease Dominant-Negative Mutation Electron Microscopy Epithelial Cells Epstein-Barr Virus Infections Family Fibrosis Funding Gelatinase B Gene Expression Genes Genetic Transcription Genome Growth Hamman-Rich syndrome Hand Herpesviridae Herpesviridae Infections Human Human Herpesvirus 4 Immunologist Incidence Individual Infection Infectious Agent Inflammatory Integrins Interferon Type II Lead Life Link Literature Localized Lung Lung diseases Lytic Matrix Metalloproteinases Mediating Medical Membrane Membrane Proteins Metalloproteases Microfluidics Molecular Molecular Profiling Morphology Mus Nuclear Numbers Pathogenesis Pathologist Pathway interactions Patients Peptides Phase Phenotype Prevalence Proteins Publications Pulmonary Fibrosis Rate Reporting Research Research Personnel Respiratory Failure Role Secondary to Sequence Homology Signal Transduction Pathway Simplexvirus Source Staining method Stains TP53 gene The science of Mycology Transcription Factor AP-1 Transcriptional Activation Transgenic Mice Transgenic Organisms Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States United States National Institutes of Health Viral Viral Antigens Viral Genes Work alveolar type II cell cytokine established cell line fibrogenesis human TGFB1 protein human TNF protein in vivo lung development lung injury microbial mortality mouse model programs response skills transcription factor virology

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a common progressive fibrotic lung disease with a dismal 50% 3-year mortality rate. Obviously, the cause of IPF is unknown; however, there are several recent publications documenting a positive correlation between Epstein-Barr virus (EBV) infection and IPF. There is virtually no literature demonstrating how herpesvirus infections contribute to the pathogenesis of lung fibrosis in animal models or in patients. Our hypothesis is that EBV enhances lung fibrogenesis through expression of either the latent or lytic EBV peptides, LMP-1 and Zta, that influence the expression and/or activity of transforming growth factor beta-1 (TGF-beta-1), metalloproteinase (MMP), and p53, molecules known to mediate fibrosis. LMP-1 is a membrane-associated peptide expressed on the surface of cells infected with EBV, and is expressed in alveolar type II (AT-II) epithelial cells in patients with IPF. LMP-1 has tumor necrosis factor alpha-like (TNF) activity, which is centrally important since TNF clearly has a role the pathobiology of lung fibrosis in humans and animal models. The replicative cycle of EBV is initiated by expression of the viral transcription factor Zta. Zta is a protein that displays sequence homology with proteins of the AP-1 family and activates the transcription of viral genes and profibrotic cellular genes such as TGF-beta-1 and MMP-9. TGF-beta-1 secretion and activation is a major focus of this proposal because it has been repeatedly implicated in lung fibrogenesis. In addition, Zta inactivates p53, which can lead to release of inflammatory and fibrogenic factors. Our data demonstrating that a transgenic mouse expressing dominant-negative p53 in AT-II cells exacerbates lung fibrosis in response to bleomycin, agrees with the possibility that Zta promotes fibrogenesis by inactivating p53. This proposal will define the pathways induced by LMP-1 and Zta, that AT-II pulmonary epithelial cells utilize to express and activate TGF-beta-1; will show how Zta-mediated inactivation of p53 enhances expression of pro-fibrotic cytokines in lung epithelial cells; and will demonstrate using a transgenic mouse model that in vivo expression of LMP-1 and Zta in type II epithelial cells recapitulates the fibrogenesis observed with murine EBV infection. There are currently no proven medicinal therapies for the treatment of IPF. Defining the mechanisms through which EBV gene products promote IPF will provide new options for the treatment of this fatal disease.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种常见的进行性纤维化肺部疾病，其3年死亡率为50％。显然，IPF的原因是未知的。但是，最近有几个出版物记录了爱泼斯坦 - 巴尔病毒（EBV）感染与IPF之间存在正相关的。几乎没有文献证明了疱疹病毒感染如何有助于动物模型或患者中肺纤维化的发病机理。我们的假设是，EBV通过表达潜在的或裂解的EBV肽LMP-1和ZTA来增强肺纤维发生，从而影响转化生长因子β-1（TGF-BETA-1），金属蛋白酶（MMP）和p53的表达和/或活性。 LMP-1是一种与膜相关的肽，该肽在感染EBV的细胞表面表达，并在IPF患者的II型肺泡II型（AT-II）上皮细胞中表达。 LMP-1具有肿瘤坏死因子α样（TNF）活性，这非常重要，因为TNF显然在人类和动物模型中具有肺纤维化的病理学作用。 EBV的复制循环是通过病毒转录因子ZTA的表达引发的。 ZTA是一种蛋白质，它显示与AP-1家族的蛋白质序列同源性，并激活病毒基因的转录和纤维化细胞基因，例如TGF-BETA-1和MMP-9。 TGF-BETA-1分泌和激活是该提案的主要重点，因为它已反复与肺纤维发生有关。另外，ZTA使p53失活，这可能导致炎症和纤维造因子的释放。我们的数据表明，AT-II细胞中表达显性阴性p53的转基因小鼠加剧了肺纤维化对博来霉素的响应，ZTA可能通过失活p53促进纤维发生的可能性。该建议将定义LMP-1和ZTA引起的途径，即AT-II肺上皮细胞用来表达和激活TGF-BETA-1；将显示ZTA介导的p53失活如何增强肺上皮细胞中促纤维化细胞因子的表达；并将使用转基因小鼠模型证明，该模型在II型上皮细胞中的体内表达LMP-1和ZTA可概括鼠EBV感染观察到的纤维发生。目前尚无对IPF治疗的证明药物疗法。定义EBV基因产品促进IPF的机制将为治疗这种致命疾病提供新的选择。