Pathways of Death and Survival in EBV B Cell Lymphomas

EBV B 细胞淋巴瘤的死亡和生存途径

• 批准号: 7101901
• 负责人: Olivia M Martinez
• 金额: $ 25.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-07 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101901
• 关键词: AP1 protein; B cell lymphoma; CD95 molecule; DNA binding protein; Epstein Barr virus; JAK kinase; SDS polyacrylamide gel electrophoresis; apoptosis; biological signal transduction; gel mobility shift assay; gene deletion mutation; gene expression; human subject; interleukin 10; latent virus infection; mutant; nuclear factor kappa beta; point mutation; protein protein interaction; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): Epstein Barr virus (EBV) is a gammaherpes virus that is associated with multiple human malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, some non-Hodgkin's lymphomas, and B cell lymphomas in bone marrow and solid organ recipients and patients with AIDS. In immunosuppressed and immunocompromised individuals the prevailing view is that impaired cellular immunity permits uncontrolled expansion of EBV-infected B cells. However, alterations in EBV-infected B cells that provide growth and survival advantages could also contribute to lymphomagenesis. Accordingly, we have demonstrated that EBV-infected B cell lines established from patients with post-transplant lymphoproliferative disorder (LPD) have constitutive activation of the Jak/STAT signal transduction pathway that is associated with cytokine-mediated cellular growth. In addition, the EBV-infected B cell lines show marked resistance to induction of apoptosis through the Fas/Fas ligand and TRAIL/DR pathways. Importantly, establishment of a latent EBV infection is sufficient to confer resistant to previously sensitive cells. Moreover, resistance to Fas-induced apoptosis correlates with expression of the natural LMP1 variants associated with increased AP-1 activation. The long-term objectivity of this work is to understand how EBV promotes the growth and survival of EBV-associated B cell lymphomas. The hypothesis is that natural LMP1 variants have differential ability to modulate pathways of apoptosis. Further, we hypothesize that LMP1 associates with Jak kinases and is sufficient for STAT activation and IL-10 production. Specific Aim 1 will determine the capacity of natural LMP1 variants to protect from intrinsic and extrinsic apoptotic stimuli. The ability of LMP1 variants to activate NFKappaB, AP-1 and modulate death receptor proximal and downstream regulators of apoptosis will be determined. Specific Aim 2 will determine the role of LMP1, and its natural variants, in activation of the Jak/STAT pathway and IL-10 expression. Elucidation of the pathways of cell death and survival in EBV-infected B cells will provide opportunities for the rational design of new therapeutics to treat EBV+ B cell lymphomas.

描述（由申请人提供）：Epstein Barr Virus（EBV）是一种伽马广播病毒，与包括伯基特淋巴瘤，鼻咽癌，霍奇奇病，霍奇金病，一些非霍奇金的淋巴瘤和骨骼骨骼的B细胞淋巴瘤和辅助器官和AIDS患者的多种人类恶性肿瘤有关。在免疫抑制和免疫功能低下的个体中，普遍的观点是细胞免疫允许不受控制的EBV感染的B细胞扩张。但是，提供生长和生存优势的EBV感染的B细胞的改变也可能导致淋巴细胞化。因此，我们已经证明，从移植后淋巴细胞增生障碍（LPD）患者建立的EBV感染的B细胞系具有与细胞因子介导的细胞生长有关的JAK/STAT信号转导途径的本构激活。此外，EBV感染的B细胞系显示了通过FAS/FAS配体和TRAIL/DR途径诱导凋亡的明显抗性。重要的是，建立潜在的EBV感染足以赋予对先前敏感细胞的抗性。此外，对FAS诱导的凋亡的抗性与与AP-1激活增加有关的天然LMP1变体的表达相关。这项工作的长期客观性是了解EBV如何促进与EBV相关的B细胞淋巴瘤的生长和存活。假设是天然LMP1变体具有调节凋亡途径的差异能力。此外，我们假设LMP1与JAK激酶相关，并且足以用于统计激活和IL-10产生。特定的目标1将确定天然LMP1变体的能力，以防止内在和外部凋亡刺激。 LMP1变体激活NFKAPPAB，AP-1和调节凋亡的死亡受体近端和下游调节剂的能力将得到确定。具体目标2将确定LMP1及其自然变体在激活JAK/STAT途径和IL-10表达中的作用。在EBV感染的B细胞中阐明细胞死亡和生存的途径将为新疗法的理性设计提供了治疗EBV+ B细胞淋巴瘤的机会。