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.

为了探索驱动静止B细胞进入细胞周期的分子事件，我们采用了一种改进的减法克隆策略来鉴定新的基因，这些基因的表达通过CD40被B细胞激活调控，CD40与激活T细胞瞬时表达的CD40配体相互作用。在过去的两年里，我们重点研究了Clast1和Clast5基因在体内的功能。来自Clast1转基因小鼠的B细胞对抗原受体信号传导具有高反应性。此外，对t依赖性抗原的初级和次级免疫反应都增强了。这些初步发现有力地提示了Clast1在增强B细胞应答中的作用。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细胞对各种刺激的反应受损。骨髓中的祖B细胞对IL-7的生长反应显著降低。这些结果表明，Clast5是B细胞活化的负调节因子，可能决定B细胞反应的阈值。我们正在培育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。

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) 基因的表达可抑制自发性肺转移而不影响致瘤性”肿瘤学报告。

Kawamura, K., O-Wang, J.et al.: "The error-prone DNA polymerase ζ catalytic subunit(Rev3)gene is ubiquitously expressed in normal and malignant human tissues"Int. J. Oncology. 18. 97-103 (2001)

Kawamura, K., O-Wang, J. 等人：“易错 DNA 聚合酶 z 催化亚基 (Rev3) 基因在正常和恶性人体组织中普遍表达”Int. J. Oncology。 (2001)

Kawamura, K., O-Wang, J.et al.: "Sez4 gene encoding an elongation subunit of DNA polymerase ζ is required for normal embryogenesis"Genes to Cells. 6. 99-106 (2001)

Kawamura, K., O-Wang, J. 等人：“正常胚胎发生需要编码 DNA 聚合酶 z 延伸亚基的 Sez4 基因”Genes to Cells. 6. 99-106 (2001)。

Tada, Y., O-Wang, J.et al.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity"Cancer Gene Ther.. (in press).

Tada, Y., O-Wang, J.等人：“表达 Fas 配体的肿瘤在接种的宿主中诱导肿瘤特异性保护性免疫，但接种凋亡肿瘤会抑制抗肿瘤免疫”Cancer Gene Ther..（出版中）