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Analysis of Islet Development Using Transgenic Mice

使用转基因小鼠进行胰岛发育分析

基本信息

批准号：
10671036
负责人：
YAMAOKA Takashi
金额：
$ 1.6万
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：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671036/
关键词：
Pancreatic islets Pancreatic β cells Transgenic mouse TGF-β Activin Interferon-γ Pax6 Reg I 糖尿病アポトーシス腫瘍発生発生工学サイトカイン Pax-6

项目摘要

(1) Glucagon promoter/active TGF-β-transgenic NOD mouse : The rate of onset of type 1 diabetes decreased because of T-cell suppression by TGF-β, and islet hypoplasia was induced by the suppressive effect of TGF-β on the growth of islets.(2) Insulin promoter/dominant negative, constitutively active, or normal activin receptor-transgenic mice : In transgenic mice expressing activin-receptor mutants, islets were hypoplastic, whereas transgenic mice expressing normal activin receptor did not show any abnormality. Therefore, appropriate intensity of activin signal is necessary for normal development of islets.(3) Glucagon promoter/interferon-γ-transgenic mouse : Interferon-γ directly impaired β cells without lymphocytes and stimulated the proliferation of immature β-cells, leading to islet remodeling.(4) Insulin promoter or Pdx1 promoter/Pax6-transgenic mice : In insulin promoter/Pax6-transgenic mice, β-cell differentiation was impaired. In Pdx1 promoter/Pax6-transgenic mice, epithelial hyperplasia of pancreatic ducts and cystic adenoma were observed, in addition to the decrease in the number of β cells. It was suggested that Pax6 has a dual action on islet development : one is the stimulation of proliferation of islet precursor cells and the other is the induction of α-cell phenotypes.(5) Glucagon promoter/Reg I-transgenic mouse : Overexpression of Reg I induced β-cell apoptosis, and diabetes. Furthermore, excessive secretion of Reg I resulted in diverse malignant tumors. The tumor-promoting activity of Reg I protein should be considered for its possible clinical applications.

(1)胰高血糖素启动子/活性TGF-β转基因NOD小鼠：由于TGF-β抑制T细胞，1型糖尿病的发病率降低，TGF-β对胰岛生长的抑制作用诱导胰岛发育不全。(2)胰岛素启动子/显性阴性、组成型活性或正常激活素受体转基因小鼠：在表达激活素受体突变体的转基因小鼠中，胰岛发育不良，而表达正常激活素受体的转基因小鼠未显示任何异常。因此，适当强度的激活素信号是胰岛正常发育所必需的。(3)胰高血糖素启动子/干扰素-γ转基因小鼠：干扰素-γ直接损害不含淋巴细胞的β细胞，并刺激未成熟β细胞的增殖，导致胰岛重塑。(4)胰岛素启动子或Pdx 1启动子/Pax 6转基因小鼠：在胰岛素启动子/Pax 6转基因小鼠中，β细胞分化受损。在Pdx 1 promoter/Pax 6转基因小鼠中，除了β细胞数量减少外，还观察到胰腺导管上皮增生和囊性腺瘤。提示Pax 6对胰岛发育具有双重作用：一是刺激胰岛前体细胞增殖，二是诱导α细胞表型。(5)胰高血糖素启动子/Reg I转基因小鼠：Reg I过表达诱导β细胞凋亡和糖尿病。此外，Reg I的过度分泌导致多种恶性肿瘤。Reg I蛋白的促肿瘤活性应考虑其可能的临床应用。