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Molecular mechanisms for pancreatic beta cell failure・a viewpoint from endoplasmic reticulum stress

Molecular mechanisms for pancreatic beta cell failure・a viewpoint from endoplasmic reticulum stress
胰腺β细胞衰竭的分子机制·内质网应激的观点
批准号:
17390258
负责人:
OKA Yoshitomo
金额:
$9.6万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
2005
资助国家:
日本
项目状态:
已结题
起止时间:
2005 至 2006

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中文摘要
翻译
Wolfram综合征是一种常染色体隐性遗传病,与糖尿病和视神经萎缩相关,是由编码内质网(ER)膜蛋白的WFS1基因突变引起的。在此,我们报道了wfs1基因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ER应激反应增强。我们用wfs1缺陷小鼠与表达猴病毒40大T抗原的小鼠杂交,建立了wfs1缺陷的MIN6克隆性(β-细胞)。这些细胞在内质网应激反应中表现出与wfs1缺乏的胰岛相同的变化,WFS1蛋白的重新表达或内质网应激的主要调节因子GRP78的过表达逆转了这一变化。相反,这些变化既不存在于心脏、骨骼肌,也不存在于WFS1缺乏的棕色脂肪组织中。内质网应激增强导致突变型胰岛caspase3裂解增加,BrdU掺入减少,表明突变型胰岛细胞凋亡过程加快,细胞周期进程受阻。这些变化与wfs1缺陷的胰岛和克隆性β细胞中p21^<CIP1和gt;的表达增加有关。用内质网应激诱导剂thapsigargin处理胰岛后,p21^<CIP1>表达上调,p21^<CIP1>强迫表达导致MIN6β细胞数量减少,提示内质网应激诱导p21^<CIP1>表达增加参与突变胰岛β细胞的丢失。这些数据表明,WFS1缺乏激活了β细胞的内质网应激反应,通过增加细胞凋亡和损害细胞周期进程而导致β细胞丢失。
英文摘要
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. Herein, we 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 wfs1-deficient MIN6 clonal (β-cells by crossing wfs1-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 wfs1-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 WFS 1-deficiency. The enhanced ER stress results in increased caspase 3 cleavage and reduced BrdU incorporation in the mutant islets, indicating accelerated apoptotic processes and impaired cell cycle progression in the mutant islets. These changes are associated with increased expression of p21^<CIP1> in wfs1-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21^<CIP1>, and forced expression of p21^<CIP1> resulted in reduction in 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.
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DOI: 10.1677/jme.1.02189
发表时间: 2007-02-01
期刊: JOURNAL OF MOLECULAR ENDOCRINOLOGY
影响因子: 3.5
作者: [Takahashi, Rui, Ishihara, Hisamitsu, Oka, Yoshitomo]
通讯作者: Oka, Yoshitomo
DOI: 10.1530/eje.1.01945
发表时间: 2005-07-01
期刊: EUROPEAN JOURNAL OF ENDOCRINOLOGY
影响因子: 5.8
作者: [Ueda, K, Kawano, J, Tanizawa, Y]
通讯作者: Tanizawa, Y
DOI: 10.1016/j.bbrc.2004.11.047
发表时间: 2005-01-14
期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子: 3.1
作者: [Imai, J, Katagiri, H, Oka, Y]
通讯作者: Oka, Y
WFS1-deficiency enhances endoplasmic reticulum stress, triggers apoptotic pathway and impairs cell cycle progression specifically in pancreatic β-cells.
WFS1 缺陷会增强内质网应激,触发细胞凋亡途径并损害细胞周期进程,特别是在胰腺 β 细胞中。
DOI: --
发表时间: 2006
期刊: Hum Mol Genet 15・10
影响因子: --
作者: [Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D, Tokita A, Satake C, Tashiro F, Katagiri H, Aburatani H, Miyazaki J-I, Oka Y]
通讯作者: Oka Y
共 9 条
    Pancreatic β cell impairment and adaptation of type 2 diabetes mellitus in overnutrition era
    • 批准号:
      19209034
    • 项目类别:
      Grant-in-Aid for Scientific Research (A)
    • 资助金额:
      $31.78万
    • 财政年份:
      2007
    • 负责人:
      OKA Yoshitomo
    • 依托单位:
    Studies on mechanisms of insulin-stimulated glucose transport : analysis of downstream signaling and real-time monitoring of GLUT4 translocation
    • 批准号:
      13470226
    • 项目类别:
      Grant-in-Aid for Scientific Research (B)
    • 资助金额:
      $10.37万
    • 财政年份:
      2001
    • 负责人:
      OKA Yoshitomo
    • 依托单位:
    Elucidation of diabetes-related genes
    • 批准号:
      13204062
    • 项目类别:
      Grant-in-Aid for Scientific Research on Priority Areas
    • 资助金额:
      $21.44万
    • 财政年份:
      2001
    • 负责人:
      OKA Yoshitomo
    • 依托单位:
    Generation of Wolfram syndrome mice, aiming at development of new therapeutics for diabetes through preserving pancreatic beta cells
    海外基金