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，并且是令人着迷的范式 宿主病毒相互作用的研究。氧化应激对于病毒介导的肿瘤发生至关重要，而对于EBV是必不可少的 B细胞的转化。活性氧（ROS）由EBV编码的产物独立诱导 LMP1，EBNA1/2和EBV潜伏期中的Ebers。我们最新的出版物首次展示了主人 抗氧化途径Keap1-NRF2赞助以激活病毒转化的细胞。在来自 母体R15，我们最近表明，LMP1通过NFκB和AP1轴影响p62的表达。在这个 补充项目，我们将检验以下假设：EBV产生的ROS触发Keap1-的激活 NRF2途径代表了EBV潜伏期中p62诱导同样重要的机制。目标 该项目的目的是解决如何在EBV延迟中激活KEAP1-NRF2途径，并进一步定义其角色 在p62（和其他目标）转录激活中，其长期目标是确定调节的新因素 EBV-host的相互作用，可以作为治疗EBV相关疾病的潜在背景特异性目标 恶性肿瘤。该项目的直接预期结果是KEAP1-NRF2的新作用的定义 EBV潜在感染中的抗氧化防御。这项研究很重要，因为披露了EBV如何控制余额 在氧化应激和抗氧化剂防御之间将大大提高我们对EBV潜伏期的理解和 发病。长期追求可能通过针对这些过程及其与之互动来制定策略 用于治疗应用的其他细胞机制。