Transcriptional Activation of p62 by the master antioxidant NRF2 in EBV latency

EBV潜伏期主要抗氧化剂NRF2对p62的转录激活

• 批准号: 10726975
• 负责人: Ling Wang
• 金额: $ 8.24万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10726975
• 关键词: AIDS related cancer; Address; Aging; Antioxidants; Autophagocytosis; B-Lymphocytes; Biochemistry and Cellular Biology; Biomedical Research; Cancer Biology; Cell Differentiation process; Cell Line; Cell Survival; Cell physiology; Cessation of life; Clinical; DNA Damage; Development; Disease; EBV-associated disease; Epithelial Cells; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Epstein-Barr pathogenesis; Equilibrium; Experimental Designs; Flow Cytometry; Genetic Transcription; Goals; Homeostasis; Human Herpesvirus 4; I Kappa B-Alpha; Image; Immunity; Immunology; Infection Control; Inflammation; LMP1; Latent virus infection phase; Left; Lymphoid Cell; Lymphoma; Lytic; Maintenance; Malignant Neoplasms; Mediating; Mitochondria; Modeling; Molecular and Cellular Biology; Obesity; Outcome; Oxidation-Reduction; Oxidative Stress; Parents; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Problem Solving; Process; Production; Property; Publications; Publishing; Quantitative Evaluations; Reactive Oxygen Species; Role; Series; Signal Transduction; Students; TNFRSF5 gene; TRAF6 gene; Techniques; Testing; Therapeutic; Thinking; Time; Training; Transcription Factor AP-1; Transcriptional Activation; Viral; Viral Pathogenesis; Virus; Writing; bioimaging; cell transformation; design; fascinate; improved; interest; neurotrophic factor; novel; novel therapeutic intervention; osteoclastogenesis; p65; parent project; pathogen; response; student training; transcription factor; transforming virus; tumorigenesis; virus host interaction

Project Summary EBV infection is associated with a panel of diseases and cancers, and serves as a fascinating paradigm for the study of host-virus interactions. Oxidative stress is essential for virus-mediated oncogenesis, and for EBV transformation of B cells. Reactive oxygen species (ROS) are independently induced by EBV-encoded products LMP1, EBNA1/2, and EBERs in EBV latency. Our most recent publication shows for the first time that the master antioxidant pathway Keap1-NRF2 is spontaneously activated in virus-transformed cells. With the support from the parent R15, we have shown recently that LMP1 induces p62 expression via NFκB and AP1 axes. In this supplementary project, we will test the hypothesis that EBV-produced ROS trigger the activation of the Keap1- NRF2 pathway that represents an equally important mechanism for p62 induction in EBV latency. The objective of this project is to address how the Keap1-NRF2 pathway is activated in EBV latency, and further define its role in p62 (and other targets) transcriptional activation, with the long-term goal to identify novel factors that regulate EBV-host interaction and may serve as potential context-specific targets for treating EBV-associated diseases and malignancies. The proximate expected outcome of this project is the definition of novel roles of the Keap1-NRF2 antioxidant defense in EBV latent infection. This study is significant in that disclosing how EBV controls the balance between oxidative stress and antioxidant defense will greatly improve our understanding of EBV latency and pathogenesis. Long-term pursuits may develop strategies by targeting these processes and their interaction with other cellular mechanisms for therapeutic applications.

项目摘要 EBV感染与一系列疾病和癌症有关，是一个迷人的范例 研究宿主与病毒的相互作用。氧化应激对病毒介导的肿瘤发生和EBV是必不可少的 B细胞的转化。活性氧簇(ROS)是由EBV编码产物独立诱导的 EBV潜伏期的LMP1、EBNA1/2和EBERS。我们最新的出版物首次表明，大师 在病毒转化的细胞中，抗氧化途径Keap1-NRF2被自发激活。得到了来自 亲本R15，我们最近发现LMP1通过核因子κB和AP1轴诱导p62的表达。在这 补充项目，我们将检验EBV产生的ROS触发Keap1激活的假设。 Nrf2途径代表了EBV潜伏期中p62诱导的一个同样重要的机制。目标是 本项目的重点是解决Keap1-NRF2通路是如何在EBV潜伏期被激活的，并进一步定义其作用 在p62(和其他靶点)转录激活中，长期目标是识别调节 EBV-宿主相互作用，可作为治疗EBV相关疾病的潜在上下文特定靶点 恶性肿瘤。该项目最接近的预期结果是定义Keap1-NRF2的新角色 EB病毒潜伏感染中的抗氧化防御。这项研究的意义在于揭示了EBV是如何控制平衡的 氧化应激和抗氧化防御之间的关系将极大地提高我们对EBV潜伏期和 发病机制。长期的追求可能会通过以这些过程为目标及其与 用于治疗应用的其他细胞机制。