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感染与一组疾病和癌症相关，并作为一个迷人的范例， 研究宿主与病毒的相互作用。氧化应激对于病毒介导的肿瘤发生和EBV 转化B细胞。活性氧（ROS）是由EBV编码的产物独立诱导的 EBV潜伏期中的LMP 1、EBNA 1/2和EBER。我们最近的出版物首次表明， 抗氧化途径Keap 1-NRF 2在病毒转化细胞中自发激活。的支持下 亲本R15，我们最近发现LMP 1通过NFκB和AP 1轴诱导p62表达。在这 作为补充项目，我们将测试EBV产生的ROS触发Keap 1激活的假设， NRF 2通路代表EBV潜伏期中p62诱导的同等重要机制。客观 本项目的目的是解决Keap 1-NRF 2通路在EBV潜伏期中是如何激活的，并进一步确定其作用 在p62（和其他目标）转录激活，长期目标是确定新的因素，调节 EBV-宿主相互作用，并可作为治疗EBV相关疾病的潜在背景特异性靶点， 恶性肿瘤该项目的最接近的预期结果是定义Keap 1-NRF 2的新作用 EB病毒潜伏感染中的抗氧化防御。本研究对于揭示EBV如何控制这种平衡具有重要意义 氧化应激和抗氧化防御之间的联系将大大提高我们对EBV潜伏期的理解， 发病机制长期追求可以通过针对这些过程及其与 用于治疗应用的其他细胞机制。