Functional analysis of novel genes involved in the regulation of B cell activation and death

参与 B 细胞激活和死亡调节的新基因的功能分析

• 批准号: 13670328
• 负责人: OH Keiyou
• 金额: $ 2.24万
• 依托单位: Chiba Cancer Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670328/
• 关键词: lymphocyte; proliferation; gene expression; immune response; transcription factor; CD40; B cell antigen receptor; 免疫学; 遺伝子; アポトーシス; シグナル伝達

To explore the molecular events that drive a resting B cell to enter the cell cycle, we have employed a modified subtractive cloning strategy to identify novel genes whose expression is regulated upon B cell activation through CD40, which interacts with CD40 ligand transiently expressed by activated T cells. In the past two years, we focused on the function in vivo of Clast1 and Clast5 genes. B cells from Clast1 tratnsgenic mice are hyper-reactive to antigen receptor signaling. In addition, both primary and secondary immune responses to T-dependent antigens are enhanced. These preliminary findings strongly suggest a role for Clast1 in augmenting B cell responses. In Clast5 transgenic mice, the size and cell number of both spleen and thymus are greatly reduced. Moreover, B cell responses to a variety of stimuli are impaired. Progenitor B cells in the bone marrow have a significantly reduced growth response to IL-7. These results indicate that Clast5 is a negative regulator of B cell activation and may serve to determine the threshold of B cell responses. We are in the process of generating Clast1 and Clast5 knock out mice.

为了探索驱动静息 B 细胞进入细胞周期的分子事件，我们采用了改良的消减克隆策略来鉴定新基因，其表达通过 CD40 在 B 细胞激活时受到调节，CD40 与激活的 T 瞬时表达的 CD40 配体相互作用。细胞。近两年我们主要关注Clast1和Clast5基因的体内功能。来自 Clast1 转基因小鼠的 B 细胞对抗原受体信号传导高度反应。此外，对 T 依赖性抗原的初级和次级免疫反应均得到增强。这些初步发现强烈表明 Clast1 在增强 B 细胞反应中的作用。在Clast5转基因小鼠中，脾脏和胸腺的大小和细胞数量都大大减少。此外，B 细胞对多种刺激的反应也受到损害。骨髓中的 B 祖细胞对 IL-7 的生长反应显着降低。这些结果表明 Clast5 是 B 细胞激活的负调节因子，可用于确定 B 细胞反应的阈值。我们正在生成 Clast1 和 Clast5 敲除小鼠。

项目成果

Tada, Y., O-Wang, J.et al.: "Expression of the TNF-(alpha) gene on mouse lung carcinoma cells suppresses spontaneous lung metastasis without affecting tumorigenicity"Oncology Report. 9. 585-588 (2002)

Tada, Y., O-Wang, J.等人：“小鼠肺癌细胞上TNF-α基因的表达抑制自发性肺转移而不影响致瘤性”肿瘤学报告。

Seimuya, M., O-Wang, J.et al.: "Clast5/Stra13 is a negative regulator of B lymphocyte activation"biochem.Biophys.Res.Commun.. 292. 121-127 (2002)

Seimuya，M.，O-Wang，J.等：“Clast5/Stra13 是 B 淋巴细胞活化的负调节因子”biochem.Biophys.Res.Commun.. 292. 121-127 (2002)

Jiyang O-Wang, Takeshi Watanabe: "Antigen presentation to Lymphocytes"Neture Publishing Group. 5 (2001)

Jiyang O-Wang、Takeshi Watanabe：“抗原呈递给淋巴细胞”Neture 出版集团。

Tada, Y., O-Wang, J.et al.: "A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells"J. Immunal.. 169. 2241-2245 (2002)

Tada, Y., O-Wang, J. 等人：“Fas 配体在促进树突状细胞获取抗原方面的新作用”J.

O-Wang, J., Watanabe, T.: "Antigen Presentation to lymphocytes"Nature Publishing Group. 5 (2001)

O-Wang，J.，Watanabe，T.：“抗原呈递至淋巴细胞”自然出版集团。