Project/Area Number |
17590264
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Pathological medical chemistry
|
Research Institution | Tohoku University |
Principal Investigator |
ISHIHARA Hisamitsu Tohoku University Hospital, Lecturer, 病院, 講師 (60361086)
|
Co-Investigator(Kenkyū-buntansha) |
OGIHARA Takehide Tohoku University, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (40361068)
TAMURA Akira Tohoku University Hospital, Research Associate, 病院・助手 (00375023)
|
Project Period (FY) |
2005 – 2006
|
Project Status |
Completed (Fiscal Year 2006)
|
Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
|
Keywords | Diabetes Mellitus / Pancreatic Islet / Signal Transduction / 膵ランゲルハンス島 / インスリン分泌 / グルカゴン分泌 / 小胞体ストレス / アポトーシス / マイクロアレイ / カルシウム / 分子生物学 |
Research Abstract |
Establishment of WFS1-deficient insulinoma cell lines. To examine the influence of WFS1-deficiency specifically in a homogenous β-cell population, β-cell lines were established by crossing wfs1^<-/-> mice with IT6 mice expressing simian virus 40 large T antigen under the insulin promoter. We found impaired insulin secretion in response to high glucose, which was recovered by adenovirus-mediated expression of wild-type WFS 1 but not of mutant WFS1 proteins found in Wolfram-syndrome patients. Role of WFS1 protein in intracellular calcium homeostasis. We analyzed WFS1-knockdown and-overexpressing HEK293 cells, and found that WFS1 protein modulates [Ca^<2+>]_<er> by positively regulating the ER Ca^<2+> uptake, which is associated with changes in the [Ca^<2+>]_<cyt> response evoked by Ca^<2+> store depletion. Identification of the translational suppressor 4E-BP1 as a pro-survival factor in β-cells under ER stress. Expression profiling in WFS1-deficient islets revealed increased 4E-BPI expression. We found that expression of 4E-BP1 was also enhanced in islets under ER stress in mouse models of diabetes. 4E-BP1 induction was found to be mediated by the transcription factor ATF4. 4E-BP1-deficient MIN6 β-cells were more vulnerable to apoptosis triggered by ER stress, with greater induction of C/EBP homologue protein. Furthermore, Eif4ebp1 deletion exacerbated hyperglycemia, with accelerated (3-cell failure, in mouse diabetes models with ER stress. Thus, 4E-BP1 induction is a pro-survival signal for (3-cells under ER stress and a potential therapeutic target for diabetes. Increased glucagon secretion from WFS1-deficient islets. Pyruvate was previously shown to stimulate glucagon secretion. In this study, we found increased alpha cell numbers and enhanced pyruvate-stimulated glucagon secretion in WFS1-deficient islets. Multiple abnormalities are suggested to contribute development of diabetes in the mouse model of Wolfram syndrome.
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