EPSTEIN BARR VIRUS LMP1 MEDIATED ONCOGENICITY

Epstein Barr 病毒 LMP1 介导的致癌性

• 批准号: 6776477
• 负责人: ELLIOTT D KIEFF
• 金额: $ 72.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-20 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776477
• 关键词: AP1 protein; B lymphocyte; CD40 molecule; Caenorhabditis elegans; Epstein Barr virus; I kappa B beta; apoptosis; cAMP response element binding protein; cell membrane; clinical research; cytokine receptors; cytoskeleton; epidermal growth factor; genetic promoter element; genetic transcription; genetically modified animals; growth factor receptors; human subject; laboratory mouse; membrane proteins; neoplasm /cancer genetics; nuclear factor kappa beta; recombinant virus; tumor necrosis factor alpha; viral carcinogenesis; virus genetics; virus protein

DESCRIPTION: (as per abstract) The objective is to develop sufficient knowledge of the molecular mechanisms by which LMP1 alters cell growth and of the effects of inhibiting those mechanisms so as to design screens for inhibitors that might be effective in treating EBV associated malignancies. The specific goals are to: (1) Use recombinant EBV based genetics to clarify the role of specific LMP1 amino acids (aa) in primary B lymphocyte growth transformation. The focus will be on aa between transformation effector site 1 (TES1) and TES2, TES1, TES2 and aa within the transmembrane domains. (2) Determine whether LMP1 signals through interactions with other receptors. LMP1 association with membrane rafts, with cytoskeletal elements, and with other membrane proteins, particularly TNFRs, will be investigated using genetic, biochemical, and physiological approaches. (3) Determine the mechanisms by which N-terminally truncated IkB causes apoptosis of EBV transformed cells so as to better validate inhibition of NFkB as a therapeutic target. (4) Investigate the cytoplasmic effects of LMP1, including the molecular mechanisms by which LMP1 and CD40 recruit TRAFs, modify TRAFs, activate NIK and ASK, effect NIK and ASK1 interaction with downstream kinases, and continuously signal or return to a basal state. (5) Determine the effects of LMP1 on B lymphocytes and epithelial gene expression from the changes in RNAs following expression of LMP1, LMP1 TES1, LMP1 TES2, or LMP1 with null mutations in TES1 and TES2. The importance of NFkB, AP1, CREB, or other factor activations will be evaluated by analyses of relevant promoters, e.g., TRAF1, EGFR, and CD40. The effects of LMP1TES1 and LMP1TES2 on cell gene transcription and on transformation will be compared with the effects of LMP1 and LMP1/CD40 in transgenic mice. (6) Evaluate the role of TRAF3 in LMP1, CD40, and LTbetaR signaling through observing differences in RNAs with LMP1 expression or CD40 or LTbetaR activation in TRAF3 knockout versus normal mouse cells or mice. The role of PKN in TRAF3 effects on the cell cytoskeleton, membranes, or transcription will also be assessed. (7) Investigate the role of C. elegans TRAF3 homologue in C. elegans neural function so as to enable screens for interacting genes that might identify novel TRAF functions.

描述：（根据摘要）目标是发展足够的知识 LMP 1改变细胞生长的分子机制， 来设计筛选抑制剂， 可能有效治疗EBV相关的恶性肿瘤。的具体目标 目的：（1）利用重组EB病毒基因技术，阐明特异性EB病毒的作用。 LMP 1氨基酸（aa）在原代B淋巴细胞生长转化中的作用。重点 将位于转化效应位点1（TES 1）和TES 2，TES 1， TES 2和跨膜结构域内的aa。(2)确定LMP 1是否 通过与其他受体的相互作用传递信号。LMP 1与 膜筏，与细胞骨架元件，和与其他膜蛋白， 特别是TNFRs，将使用遗传学，生物化学和生物化学方法进行研究。 生理学方法。(3)确定N-末端 截短的IkB引起EBV转化细胞的凋亡， 验证NFkB作为治疗靶标的抑制。(4)探讨 LMP 1的细胞质效应，包括LMP 1 CD 40募集TRAFs，修饰TRAFs，激活NIK和ASK，影响NIK和ASK 1 与下游激酶相互作用，并连续发出信号或返回到一个 基础状态(5)确定LMP 1对B淋巴细胞和上皮细胞的作用 来自LMP 1表达后RNA变化的基因表达，LMP 1 TES 1、LMP 1 TES 2或在TES 1和TES 2中具有无效突变的LMP 1。的重要性 NFkB、AP 1、CREB或其他因子激活的影响将通过分析 相关发起人，例如，TRAF 1、EGFR和CD 40。LMP 1 TES 1和 LMP 1 TES 2对细胞基因转录和转化的影响将与 LMP 1和LMP 1/CD 40在转基因小鼠中的作用。(6)评价的作用 TRAF 3在LMP 1、CD 40和LT β R信号传导中的作用， TRAF 3敲除中具有LMP 1表达或CD 40或LT β R活化的RNA 与正常小鼠细胞或小鼠相比。PKN在TRAF 3作用于细胞中的作用 还将评估细胞骨架、膜或转录。（七） 探讨了C. elegans TRAF 3同源基因在C.神经线虫 功能，以便能够筛选相互作用的基因， 新的TRAF功能。