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Studies on characteristics and mechanism of radiation carcinogenesis in radiosensitive strains of mice

放射敏感品系小鼠放射致癌特征及机制研究

基本信息

批准号：
11670233
负责人：
OGIU Toshiaki
金额：
$ 2.3万
依托单位：
National Institute of Radiological Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670233/
关键词：
Radiation carcinogenesis C.B-17 Scid mice DNA repair DNA-PKcs C.B-17 mice Thymic lymphoma Nochi1 Mutation 放射線発ガン Notch1 遺伝子欠失骨髄移植 Y染色体

项目摘要

The C.B-17 Scid mouse demonstrates immunodeficiency and also radio sensitivity similar to human ataxia-telangiectasia because of mutation in the DNA-PKcs gene. This strain of mice was also susceptible to radiation induction of thymic lymphomas. Therefore, characteristics of radiation carcinogenesis and molecular mechanisms were examined in this study. Scid, C.B-17 and their hybrid F1 mice were irradiated with gamma-rays and spectrum of carcinogenesis was first examined. Scid mice were extremely susceptible to the induction of thymic lymphomas by ionizing radiation, but not C.B-17 and F1 mice. Then irradiated Scid mice were transplanted with normal bone marrow cells of C.B-17 mice just after gamma-ray-irradiation to suppress induction of thymic lymphomas and thereby to examine carcinogenesis in various organs other than the thymus. This treatment completely reduced development of thymic lymphomas, but no excess of other tumors was demonstrated comparing with that in C.B-17 and F1 mice. Next, Scid mice with C3H background (C3H Scid mice) were used to examine effects of genetic background on radiosensitivity and radiation carcinogenesis. C3H Scid were demonstrated to be more radiosensitive and more susceptible to radiation induction of thymic lymphomas compared with C.B-17 Scid mice. Furthermore, presence of modifier gene was suspected Mutations of various cancer-related genes were examined with thymic lymphomas, and mutation of the Notch1 gene encoding cell surface receptor was frequently observed. Length of this gene is 45.6 kb with 34 exons. Although Genomic rearrangement was observed in about 20% of thymic lymphomas of STS and C.B-17 mice, that was more frequent in C.B-17 Scid mice. Detected rearrangements are deletion, IAP insertion and inversion. Furthermore, abnormal mRNA and protein were demonstrated in the tumors. Then, it is suggested that Notch1 gene is an oncogene, which is continuously active and may have a important role in thymic lymphomagenesis.

由于DNA-PKcs基因的突变，C.B-17SCID小鼠表现出免疫缺陷和放射敏感性，类似于人类共济失调-毛细血管扩张症。这种品系的小鼠也容易受到辐射诱导的胸腺淋巴瘤的影响。因此，本研究对辐射致癌的特点和分子机制进行了研究。对SCID、C.B-17及其杂交F1小鼠进行了伽马射线照射，并首次对其致癌谱进行了研究。SCID小鼠对电离辐射诱发胸腺淋巴瘤非常敏感，而C.B-17和F1小鼠则不敏感。然后，在伽马射线照射后，将照射后的SCID小鼠的正常骨髓细胞移植到C.B-17小鼠的正常骨髓细胞中，以抑制胸腺淋巴瘤的诱导，从而检查胸腺以外的各种器官的致癌作用。这种治疗完全减少了胸腺淋巴瘤的发展，但与C.B-17和F1小鼠相比，没有发现过多的其他肿瘤。其次，用C3HSCID小鼠(C3HSCID小鼠)检测遗传背景对辐射敏感性和辐射致癌的影响。与C.B-17SCID小鼠相比，C3HSCID小鼠对辐射更敏感，对辐射诱发胸腺淋巴瘤更敏感。此外，胸腺淋巴瘤中疑似存在修饰基因，可检测到多种癌相关基因的突变，其中编码细胞表面受体的Notch1基因突变最为常见。该基因全长45.6kb，有34个外显子。虽然在STS和C.B-17小鼠的胸腺淋巴瘤中观察到约20%的基因组重排，但在C.B-17 SCID小鼠中更常见。检测到的重排有缺失、IAP插入和倒位。此外，肿瘤组织中还存在异常的mRNA和蛋白。提示Notch1基因是一种持续活跃的癌基因，可能在胸腺淋巴肿大发生中起重要作用。