ANTIGEN-INDUCED B LYMPHOCYTE DEVELOPMENT

抗原诱导的 B 淋巴细胞发育

• 批准号: 7076174
• 负责人: DOUGLAS T FEARON
• 金额: $ 26.37万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076174
• 关键词: B lymphocyte; Burkitt' s lymphoma; CD19 molecule; antigen receptors; biological signal transduction; cell differentiation; cytokine receptors; disease /disorder model; genetically modified animals; heparan sulfate; heparin; immunologic memory; laboratory mouse; leukocyte activation /transformation; oncoproteins; protein tyrosine phosphatase; protooncogene; tetracyclines; thymus

DESCRIPTION (provided by applicant): With a long-term objective to understand the developmental stages of the B cell response to antigen, this research will focus on germinal center and memory B cells, which relate to the cardinal features of immunity, affinity maturation of the immune response and immunological memory. The specific aims are to determine: 1) the role of heparan sulfate/heparin in serving as a ligand for CD19 in the germinal center; 2) whether developmental down-regulation of SHP-1 in the germinal center B cell is required, and whether this permits signaling through a gamma-c cytokine receptor; 3) whether arrested terminal differentiation by BCL-6 is the basis for B cell memory; 4) whether signaling through a gamma-c, cytokine receptor is necessary to maintain memory B cells; and 5) whether B cells with dysregulated c-myc present as centroblast-like Burkitt lymphomas because of unique expression patterns of BCL-6 and SHP-l at this stage of development. For Aims 2-5, mice will be created in which transgenes can be inducibly expressed in a lineage-specific manner. A bacterially-derived transactivator transgene, rtTA, will be expressed only in B cells and will drive transcription of "target" transgenes in the presence of doxycycline. The target transgenes are SHP-1, dominant negative (DN) gamma-c, and wild-type and DN BCL6, all linked via an IRES to EGFP to permit visualization of transgene expression. With doubly transgenic, Fl mice, giving doxycycline will 1) up-regulate SHP-1 and DN gamma-c in germinal center B cells, allowing analysis of the role of low SHP-1 and cytokine receptor signaling in these cells; and 2) up-regulate DN gamma-c, and wild-type and DN BCL-6 in memory B cells, allowing analysis of the role of BCL-6 and cytokine receptor signaling in these cells. The understanding gained from these studies of normal B cell development will be applied to a murine model of Burkitt lymphoma to discover why translocation of c-myc at an early stage of B cell development leads to a B cell tumor at a much later stage.

描述（由申请人提供）：具有需要理解的长期目标 B 细胞对抗原反应的发育阶段，这项研究将 重点关注生发中心和记忆 B 细胞，它们与基本功能相关 免疫特征、免疫反应的亲和力成熟和 免疫记忆。具体目标是确定： 1） 硫酸乙酰肝素/肝素作为生发中心 CD19 的配体； 2) 生发中心B细胞中SHP-1是否发育下调 是必需的，以及这是否允许通过 γ-c 细胞因子发出信号 受体； 3)是否以BCL-6抑制终末分化为依据 B细胞记忆； 4) 通过γ-c、细胞因子受体的信号传导是否是 维持记忆 B 细胞所必需的； 5) B细胞是否失调 c-myc 由于独特的特性而呈现为中心母细胞样伯基特淋巴瘤 BCL-6 和 SHP-1 在此发育阶段的表达模式。为了目标 2-5，将创建小鼠，其中转基因可以诱导表达 血统特定的方式。细菌来源的反式激活子转基因，rtTA， 仅在 B 细胞中表达并驱动“目标”转录 在强力霉素存在下进行转基因。目标转基因是SHP-1， 显性失活 (DN) gamma-c、野生型和 DN BCL6，全部通过 IRES 至 EGFP 允许转基因表达可视化。与双 转基因 F1 小鼠给予多西环素将 1) 上调 SHP-1 和 DN 生发中心 B 细胞中的 γ-c，可分析低 SHP-1 的作用 以及这些细胞中的细胞因子受体信号传导； 2) 上调 DN gamma-c， 以及记忆 B 细胞中的野生型和 DN BCL-6，从而可以分析 这些细胞中的 BCL-6 和细胞因子受体信号传导。获得的理解 这些正常 B 细胞发育的研究将应用于小鼠 伯基特淋巴瘤模型以发现 c-myc 早期易位的原因 B 细胞发育阶段导致 B 细胞肿瘤处于更晚的阶段。