Regulation of Latent-Lytic Switch in EBV by ZEB

ZEB 对 EBV 中潜在裂解开关的调节

• 批准号: 7470079
• 负责人: Janet Elaine Mertz
• 金额: $ 35.01万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470079
• 关键词: Address; Antibodies; B-Lymphocytes; BZLF1 gene; BZLF1 protein, Herpesvirus 4, Human; Binding; Biological Assay; Cell Line; Cell surface; Cells; Condition; DNA Binding; Databases; Development; EBV-associated disease; EBV-associated malignancy; Elements; Epithelial; Epithelial Cells; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Gene Expression; Genes; Genome; Goals; Hairy Leukoplakia; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Immunization; Immunoglobulins; Indium; Infection; Infectious Mononucleosis; Knowledge; Lead; Length; Life Cycle Stages; Lymphocyte; Lytic; Maintenance; Malignant - descriptor; Malignant Neoplasms; Measures; Membrane Proteins; Messenger RNA; Mining; Modeling; Mutation; Nasopharynx Carcinoma; Neoplasms; Non-Hodgkin' s Lymphoma; Play; Polymerase Chain Reaction; Post-Translational Protein Processing; Production; Proteins; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Simplexvirus; Stomach Carcinoma; Switch Genes; System; Testing; Time; Tissues; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Tissue; Vaccines; Virus; base; chromatin immunoprecipitation; cis acting element; knock-down; lymphocyte proliferation; lytic replication; mutant; novel; promoter; reactivation from latency; research study; small hairpin RNA; virology

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a human gamma herpesvirus that infects most people by adulthood. Infection is associated with infectious mononucleosis, Burkitt's and non-Hodgkin's lymphomas, Hodgkin's disease, nasopharyngeal carcinoma, oral hairy leukoplakia, and some gastric carcinomas. The long-term goals of this research are (i) to elucidate mechanisms controlling latency versus lytic replication of EBV, and (ii) to apply this knowledge toward the development of new therapies for treating some EBV-associated diseases. Dr. Mertz and her colleagues have recently identified a novel cis-acting element, ZV, and its trans-acting factor, ZEB1, that play central roles in regulating EBV's latent-lytic switch gene, BZLF1, during latency and its reactivation by inducers such as TGF-beta and anti-immunoglobulins. The specific aims are the following: (i) Determine importance of ZEB1 in regulating EBV's life cycle via binding the ZV element in the BZLF1 promoter by (a) determining effects of mutations in the ZV element on establishment of latency and reactivation to lytic replication, (b) confirming ZEB1 regulates expression of the BZLF1 promoter via binding the ZV element, (c) determining the effects of ZEB1's abundance on establishment and maintenance of latency and reactivation using cell lines inducible for expression of ZEB1, and (d) looking for correlations between presence of ZEB1 and consequences of infection by EBV by measuring the abundance of ZEB1 mRNA and protein in a variety of human B-lymphocytic and epithelial normal and EBV-associated tumor tissues; and (ii) Elucidate mechanisms by which effectors of cellular signaling pathways induce latency or reactivation of EBV in part via modulating ZEB1 by (a) determining the effects of the EBV-encoded protein LMP1 on ZEB1's abundance, activity, and effects on EBV's life cycle using cells inducible for expression of LMP1 and LMP1 mutants of EBV, and b) testing models for activation of expression of the BZLF1 gene via ZEB1 by looking for correlations between expression and changes in the abundance, cellular localization, DNA-binding activity, co-purifying co-regulators, and post-translational modifications of ZEB1 after activation of cells with anti-immunoglobulins and TGF-beta. These studies should confirm our hypothesis regarding the central roles of ZEB1 and the ZV element in regulating EBV's life cycle and, possibly, lead to novel therapies for immunization against EBV and treatment of some EBV-associated diseases.

描述（由申请人提供）：Epstein-Barr病毒（EBV）是人类γ疱疹病毒，成年后大多数人感染了大多数人。感染与传染性单核细胞增多症，伯基特和非霍奇金的淋巴瘤，霍奇金氏病，鼻咽癌，口腔毛毛状白血病和一些胃癌有关。这项研究的长期目标是（i）阐明控制潜伏期与EBV裂解复制的机制，以及（ii）将这些知识应用于开发新疗法以治疗某些EBV相关疾病的新疗法。 Mertz博士和她的同事们最近确定了一种新颖的顺式作用元素ZV及其反式作用因子Zeb1，在调节EBV的潜在散热开关基因BZLF1中起着核心作用，在潜伏期中，及其在TGF-Beta和抗抗抗原蛋白等诱导剂中的重新激活中，在延迟中及其重新激活。具体目的是以下：（i）通过（a）通过（a）确定突变在ZV元素中确定突变对建立Lytic Roplication的延迟和重复的效果来确定ZEB1在调节EBV的生命周期中的重要性，（a）通过确定ZEB1的表达来确定ZEB1的表达（bzlf1启动器的表达（bzlf1 Zeb1在建立和维持潜伏和维持Zeb1表达的细胞系上的丰富性，以及（d）通过测量Zeb1的存在与EBV感染后果之间的相关性，通过测量Zeb1 mRNA和蛋白质在各种人类B-裂解的eB-lymphocycy and Ebv-sangied and Ebv-sanke rangied and Tum sangied and Tum sistrue; （ii）阐明机制，通过（a）通过（a）确定EBV代码蛋白LMP1对ZEB1的丰度，对EBV的生命周期来表达LMP1和LMP1的表达，通过（a）确定EBV编码的蛋白LMP1对ZEB1的丰度，通过（a）确定EBV的生命周期，通过（a）确定EBV代码蛋白LMP1的效果，从而阐明了细胞信号通路的效应部分，部分通过调节ZEB1诱导了潜伏期或EBV的重新激活。通过寻找丰度，细胞定位，DNA结合活性，共晶体共调节剂和ZEB1在用抗免疫球蛋白和TGF-beta激活细胞后，通过ZEB1进行BZLF1基因通过ZEB1进行的相关性。这些研究应证实我们关于Zeb1和ZV元素在调节EBV生命周期中的核心作用的假设，并可能导致对EBV的免疫免疫的新疗法以及对某些EBV相关疾病的治疗。