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Elucidation of diabetes-related genes

阐明糖尿病相关基因

基本信息

批准号：
13204062
负责人：
OKA Yoshitomo
金额：
$ 21.44万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13204062/
关键词：
Diabetes Insulin secretion pancreatic B cell Wolfram syndrome Endoplasmic reticulum stress cell cycle SNP ウェルナー症候群 GPLD1 GDH GLUD1 PPARa glutamate

项目摘要

Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. We herein report that pancreatic islets of wfs1-deficient mice exhibit increases in PKR-like ER kinase phosphorylation, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfsl-deficient MIN6 clonal β-cells by crossing wfsl-deficient mice with mice expressing simian virus 40 large T antigen in β-cells. These cells show essentially the same alterations in ER stress responses as wfsl-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of ER stress. In contrast, these changes are observed neither in heart, skeletal muscle, nor brown adipose tissues with WFS1-deficiency. The enhanced ER stress results in increased caspase 3 cleavage and reduced BrdU incorporation, indicating accelerated apoptotic processes and impaired cell cycle progression in the mutant islets. These changes are associated with increased expression of p21^<CIP1> in wfsl-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer increased p21^<CIP1> expression, and forced expression of p21^<CIP1> reduced MIN6 β-cell numbers, suggesting that the ER stress-induced increase in p21^<CIP1> expression to be involved in β-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in β-cells, causing β-cell loss through increased apoptosis and impaired cell cycle progression.

Wolfram综合征是一种与糖尿病和视神经萎缩相关的常染色体隐性遗传疾病，由编码内质网（ER）膜蛋白的WFS1基因突变引起。我们在此报告，wfs1缺陷小鼠的胰岛表现出PKR样ER激酶磷酸化，伴侣基因表达和活性XBP1蛋白水平的增加，表明增强的ER应激反应。我们通过将wfsl缺陷型小鼠与在β细胞中表达猿猴病毒40大T抗原的小鼠杂交来建立wfsl缺陷型MIN6克隆β细胞。这些细胞表现出与wfsl缺陷型胰岛基本相同的ER应激反应的改变，其通过WFSl蛋白的再表达或ER应激的主调节因子GRP78的过表达而逆转。相比之下，在WFS1缺乏的心脏、骨骼肌和棕色脂肪组织中均未观察到这些变化。增强的ER应激导致半胱天冬酶3裂解增加和BrdU掺入减少，表明突变胰岛中细胞凋亡过程加速和细胞周期进展受损。这些变化与<CIP1>wfsl缺陷型胰岛和克隆β细胞中p21 α表达增加有关。用毒胡萝卜素（一种ER应激诱导剂）处理胰岛增加p21 β<CIP1>表达，并且p21 β的强制表达<CIP1>减少MIN6 β细胞数量，这表明ER应激诱导的p21 β表达增加<CIP1>涉及突变胰岛中的β细胞损失。这些数据表明，WFS1缺陷激活了β细胞中特异性的ER应激反应，通过增加细胞凋亡和受损的细胞周期进程引起β细胞损失。