2004 Fiscal Year Final Research Report Summary
Rescue of Neuronal Cell Death by ER-stress protein over expression
Project/Area Number |
14580725
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Nerve anatomy/Neuropathology
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Research Institution | Kanazawa University |
Principal Investigator |
KITAO Yasuko Kanazawa University, Graduate School of Medical Science, Assistant Professor, 医学系研究科, 助手 (00019613)
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Co-Investigator(Kenkyū-buntansha) |
OGAWA Satoshi Kanazawa University, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (90283746)
HORI Osamu Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (60303947)
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Project Period (FY) |
2002 – 2004
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Keywords | Astrocytes / Brain ischemia / ER-stress / Gene Therapy / Glutamic acid / Ischemic tolerance |
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 altety, 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 shess in the ER (ER stress). Neurons became more vulnerable to these stresses following treatment of either cyclcheximide or the infection with an adenovirus carrying ORP150 antisense structure. In cantrast, the overexpression of ORP150 by adenovinus suppressed the neuronal cell death, and this was accompanied by the suppression of the Ca2+ eleva
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tion and proteolytic activity induced by glutamate. Further, overexpressicn of ORP150 in CA1 neurons by the adenovirus carrying ORP150-sense struciture suppressed delayed neuronal cell death after ischemia. These data suggest a possible function of ORP150 as an intracellular apparatus, which participates in a protective response in ischemic tolerance. A series of events initiated by glutamate-receptor interaction perturbs cellular homeostasis resulting in elevation of intracellular free calcium and cell death. Cells subject to such environmental change express stress proteins, which contribute importantly to maintenance of metabolic homeostasis and viability. We show that an inducible chaperone present in endoplasmic reticulum (ER), the 150 kDa oxygen-regulated protein (ORP150) is expressed both in human brain after seizure attack and in mice hippocampus after kainite administration. Using mice heterozygous for ORP150 deficiency, exposure to excitatory stimuli caused hippocampal neurons to display exaggerated elevation of cytosolic calcium accompanied by activation of μ-calpain and cathepsin B, as well as increased vulnerability to glutamate-induced cell death in vitro and decreased survival to kainate in vivo. In contrast, targeted neuronal overexpression of ORP150 suppressed each of these events, and enhanced neuronal and animal survival in parallel with diminished seizure intensity. Studies using cultured hippocampal neurons showed that ORP150 regulates cytosolic free calcium and activation of proteolytic pathways causing cell death in neurons subject to excitatory stress. Our data underscore a pivotal role for ER stress in glutamate toxicity, and pinpoint a key ER chaperone, ORP150, which orchestrates the protective stress response critical for neuronal survival. Less
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Research Products
(17 results)
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[Journal Article] Prolonged ER Stress in Hypertrophic and Failing Heart Following Aortic Constriction : Possible Contribution of ER Stress to Cardiac Myocyte Apoptosis.2004
Author(s)
Okada K, Minamino T, Tsukamoto Y, Liao Y, Hirota A, Yurtani A, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M.
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Journal Title
Circulation. 110
Pages: 705-712
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Peg3/Pw1 Is Involved in p53-mediated Cell Death Pathway in Brain Ischemia/Hypoxia.2002
Author(s)
Yamaguchi A, Taniguchi M, Hori O, Ogawa S, Tojo N, Matsuoka N, Miyake Si S, Kasai K, Sugimoto H, Tamatani M, Yamashita T, Tohyama M.
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Journal Title
J.Biol.Chem. 277
Pages: 623-629
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Transmission of cell stress from endoplasmic reticulum to mitochondria : expression of Lon protease.2002
Author(s)
Hori O, Ichinoda F, Tamatani T, Yamaguchi A, Sato N, Ozawa K, Kitao Y, Miyazaki M, Harding HP, Ron D, Tohyama M, Stern DM, Ogawa S.
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Journal Title
J.Cell Biol. 157
Pages: 1151-1160
Description
「研究成果報告書概要(欧文)」より
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