EPSTEIN BARR VIRUS LMP1 MEDIATED ONCOGENICITY

Epstein Barr 病毒 LMP1 介导的致癌性

• 批准号: 6514372
• 负责人: ELLIOTT D KIEFF
• 金额: $ 68.46万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514372
• 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 LMP1改变细胞生长和影响的分子机制 抑制这些机制，以设计抑制剂的筛选 可能有效治疗与EBV相关的恶性肿瘤。具体目标 是：（1）使用基于重组EBV的遗传学来阐明特定的作用 原代B淋巴细胞生长转化中的LMP1氨基酸（AA）。重点 将在转换效应器位点1（tes1）和tes2，tes1， 跨膜域内的TES2和AA。 （2）确定LMP1是否 通过与其他受体相互作用的信号。 LMP1关联 膜筏，带有细胞骨架元素，以及其他膜蛋白， 特别是TNFR，将使用遗传，生化和 生理方法。 （3）确定N末端的机制 截短的IKB引起EBV转化细胞的凋亡，以便更好 验证抑制NFKB作为治疗靶标。 （4）调查 LMP1的细胞质作用，包括LMP1的分子机制 和CD40招募TRAFS，修改TRAF，激活Nik并询问，效果Nik和Ask1 与下游激酶的相互作用，并连续发信号或返回到 基础状态。 （5）确定LMP1对B淋巴细胞和上皮的影响 LMP1表达后RNA的变化的基因表达 TES1，LMP1 TES2或LMP1在TES1和TES2中具有空突变。重要性 NFKB，AP1，CREB或其他因素激活将通过分析评估 相关启动子，例如TRAF1，EGFR和CD40。 LMP1TES1和 在细胞基因转录和转化上的LMP1TES2将与 LMP1和LMP1/CD40在转基因小鼠中的影响。 （6）评估 LMP1，CD40和LTBETAR信号传导中的TRAF3通过观察 带有LMP1表达或CD40或LTBETAR激活的RNA 与正常小鼠细胞或小鼠相比。 PKN在TRAF3影响细胞中的作用 还将评估细胞骨架，膜或转录。 （7） 研究秀丽隐杆线虫Traf3同源物在秀丽隐杆线虫神经中的作用 功能以使屏幕能够进行相互作用的基因，以识别 新颖的TRAF功能。