| Project/Area Number |
18390103
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Yamaguchi University |
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Principal Investigator |
TANIZAWA Yukio Yamaguchi University, Graduate School of Medicine, Professor (00217142)
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| Co-Investigator(Kenkyū-buntansha) |
YUJIRI Toshiaki Yamaguchi University, Yamaguchi University Hospital, Associate Professor (80346551)
UEDA Kohei Yamaguchi University, Yamaguchi University Health Service Center, Associate Professor (50325221)
TURU Masatoshi Yamaguchi University, Yamaguchi University Hospital, Assistant Professor (20379960)
OHTA Yasuharu Yamaguchi University, Yamaguchi University Graduate School of Medicine, Assistant Professor (60448280)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,530,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥1,830,000)
Fiscal Year 2007: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
Fiscal Year 2006: ¥8,600,000 (Direct Cost: ¥8,600,000)
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| Keywords | Wolfram Syndrome / Diabetes Mellitus / Endoplasmic reticulum stress / pancreatic β-cells / Insulin / Pioglitazone / optic atrophy / wolfram症候群 / インスリン分泌 / インスリン抵抗性 / ノックアウトマウス |
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| Research Abstract |
There are accumulating evidences that decrease in β-cell mass play roles in the development and progression of type 2 diabetes mellitus. Endoplasmic reticulum stress has recently emerged as a candidate mechanism of β-cell loss. We investigated this mechanism using Wfs1 knock-out mouse as a model. The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein, homozygous mutations of which cause selective β-cell loss in humans. The WFS1 protein is involved in ER stress responses, but the mechanism of β-cell death in WFS1-deficient β-cells is still not fully understood. Interestingly, the phenotype of Wfs1^<-/-> mice depends mainly on their genetic backgrounds. Wfs1^<-/-> mice with the C57BL/6J background do not develop overt diabetes. However, we found that when these mice become mildly obese and insulin resistant due to the agouti lethal yellow mutation (Wfs1^<-/-> A^y/a), they develop selective β-cell loss and severe insulin-deficient diabetes as early as 16 weeks of ag
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e. This β-cell loss appeared to be due to apoptosis. In A^y/a murine islets, ER chaperone Bip/GRP78 expression and EIF2□ phosphorylation increased, suggesting that obesity induced ER stress in β-cells. Expression of the Bip/GRP78 protein was further increased in Wfs1^<-/-> A^y/a mice as compared to Wfs1^<-/-> or A^y/a mice. Electron micrography revealed markedly dilated ERs and decreased insulin granules in β-cells, suggesting that insulin resistance causes ER stress, and that pancreatic β-cells lacking Wfs1 are more susceptible to ER stress-induced apoptosis. Interestingly, pioglitazone treatment almost completely prevented diabetes, and protected β-cells form apoptosis. In islets, despite no difference in ER chaperone expression, CHOP expression was reduced. Although Wolfram syndrome is a distinct disease, there may be common processes involving slow, but progressive β-cell loss in patients with type 2 diabetes mellitus, in whom insulin demands rise continuously due to insulin resistance. Investigation of this model is anticipated to provide insights into the mechanism and prevention of β-cell loss. Less
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