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Analysis of Pancreatic B-Cell Development and an Animal Model of Regeneration Therapy for Diabetes Mellitus Using Transgenic Mice

转基因小鼠胰腺 B 细胞发育分析和糖尿病再生治疗动物模型

基本信息

批准号：
13671194
负责人：
YAMAOKA Takashi
金额：
$ 2.05万
依托单位：
The University of Tokushima
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-13671194/
关键词：
Pancreatic islets Pancreatic B cells Transgenic mouse Cdk4 Activin HB-EGF Regenerative medicine Diabetes mellitus Pdx1 細胞周期 p16

项目摘要

In transnic mice expressing active Cdk4 mutant driven by the insulin promoter, B-cell area was remarkably increased by B-cell proliferation up to half of the whole pancreas area. Proliferated B cells were highly differentiated: they contained a great amount of insulin seretory granules and GLUT2 were expressed on their cell membrane. Cdk4-transgenic mice showed better glucose tolerance than normal control mice did, but neither insulinoma nor hypoglycemic symptoms occurred. Because activation of Cdk4 induced the proliferation of highly differentiated B cells. It is suggested that Cdk4 is a target molecule of regeneration therapy for diabetes mellitus.Both transgenic mice expressing dominant negative activin receptor and transgenic mice expressing activin B by the Pdx1 promoter showed islet hypoplasia and developed diabetes, suggestng that appropriate activin signaling is necessary for normal development of B cells. Therefore, apropriate concentration and timing of activin admistration should be considered for the differentiation of ES cells into pancreatic B cells.Both transgenic mice expressing dominant negative activin receptor and transgenic mice expressing HB-EGF by the Pdx1 promoter showed the dilation of pancreatic duct and bile duct. These results indicate that the proliferaion of these ductal epothelia is regulated by activin and HB-EGF. HB-EGF is probably useful for effective expansion of cultured pancreatic ductal cells as the source of B-cell precursor.

在表达由胰岛素启动子驱动的活性Cdk 4突变体的transnic小鼠中，B细胞面积因B细胞增殖而显著增加，达到整个胰腺面积的一半。纯化后的B细胞高度分化，含有大量的胰岛素分泌颗粒，细胞膜上表达GLUT 2。cdk 4转基因小鼠比正常对照小鼠表现出更好的糖耐量，但没有胰岛素瘤和低血糖症状的发生。因为Cdk 4的激活诱导了高分化B细胞的增殖。结论Cdk 4是糖尿病再生治疗的靶分子，表达显性负性激活素受体的转基因小鼠和Pdx 1启动子表达激活素B的转基因小鼠均表现为胰岛发育不全和糖尿病，提示激活素信号通路对B细胞的正常发育是必需的。因此，在ES细胞向胰腺B细胞分化时，应考虑适当的激活素浓度和时机。显性负性激活素受体转基因小鼠和通过Pdx 1启动子表达HB-EGF的转基因小鼠均表现出胰管和胆管扩张。结果表明，这些导管上皮细胞的增殖受激活素和HB-EGF的调节。HB-EGF作为B细胞前体的来源，可能对培养的胰腺导管细胞的有效扩增有用。