| Project/Area Number |
15200028
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Graduate School of Medical Science, Kanazawa University |
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Principal Investigator |
OGAWA Satoshi Kanazawa University, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (90283746)
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| Co-Investigator(Kenkyū-buntansha) |
HORI Osamu Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (60303947)
KITAO Yasuko Kanazawa University, Graduate School of Medical Science, Assistant Professor, 医学系研究科, 助手 (00019613)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000)
Fiscal Year 2005: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2004: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2003: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
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| Keywords | Astrocytes / Brain ischemia / ER-stress / Gene Therapy / Glutamic acid / Ischemic tolerance / パーキンソニズム / 小胞体関連蛋白分解 / 神経細胞死 / ドパミン / 黒質線条体神経 / グルタミン酸 / 小脳発生 / プルキンエ細胞 |
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| Research Abstract |
ORP150 is a novel stress protein localized in the endoplasmic reticulum (ER). To investigate the role of ORP150 in delayed neuronal cell death, we have examined its expression in the gerbil brain after the ischemic insult. The expression of ORP150 antigen, as well as its transcripts, was observed in the CA1 region after the occlusion of the common carotid artery, and this was enhanced by the preconditioning. In cultured neurons, exposure to either hypoxia or glutamate induced the expression of ORP150, and this was also observed by treating the culture with either thapsigargin or breferdin-A, indicating that both glutamate and hypoxia can cause stress in the ER (ER stress). Neurons became more vulnerable to these stresses following treatment of either cycloheximide or the infection with an adenovirus carrying ORP150 antisense structure, In contrast, the overexpression of ORP150 by adenovirus suppressed the neuronal cell death, and this was accompanied by the suppression of the Ca2+ elev
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ation and proteolytic activity induced by glutamate. Further, overexpression of ORP150 in CA1 neurons by the adenovirus carrying ORP150-sense structure suppressed delayed neuronal cell death after ischemia. These date suggest a possible function of ORP150 as an intracellular apparatus, which participates in a protective response in ischemic tolerance.
Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. We discuss the role of ER-stress in neuronal cell death in SNpc by introducing two models. Upregulation of Pael-Receptor in the substantia nigra pars (SNpc) of mice induces endoplasmic reticulum (ER) stress leading to a decrease in tyrosine hydroxylase and death of dopaminergic neurons. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their enhanced death in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150, suggesting parkin dysfunction result in ER-stress mediated neuronal cell death. Conversely, transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS) positive inclusions, which distributed throughout the deeper layers of cerebral cortex, hippocampal CA1, and substantia nigrta. Enhanced ER stress was observed in dopamine neurons in SNpc, accompanied with loss of neuronal viability and motor coordination. In both subregions, PAS-positive inclusions were also positive with megsin. These data suggest that enhanced ER stress causes selective vulnerability in a set of neuronal populations. Less
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