| Project/Area Number |
13670677
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Hyogo College of Medicine |
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Principal Investigator |
MATSUYAMA Tomohiro Hyogo College of Medicine, School of Medicine, Assistant Professor, 医学部, 講師 (10219529)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Hiroyuki Hyogo College of Medicine, School of Medicine, Research Associate, 医学部, 助手 (20248131)
OKAMOTO Masaya Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (30309455)
OGAWA Satoshi Kanazawa University, School of Medicine, Professor, 医学研究科, 教授 (90283746)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | medicine / neurodegenerative disease / Parkinson's disease / ER-stress / 150kd oxygen regulated protein |
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| Research Abstract |
The purpose of this study is to examine whether ER-stress responses may contribute to neuronal death in the ischemic brain injury or neurodegeneration of substantia nigra (SN) in Parkinson's disease. Cultured neurons derived from ORP150 transgenic (TG) mice were more resistant to hypoxia than those from wild-type (Wt) mice, and neurons from ORP150 -/+ mice were more vulnerable to hypoxia than those from Wt mice. The volume of cerebral infarction after ligation of middle cerebral artery in ORP150 TG mice was significantly less than that of Wt or -/+ mice. The study revealed that ORP150 protests neurons via the acceleration of BDNF secretion under ischemic environment of the brain (Nat Med, 7 : 317-313, 2001). The suppression of neuronal cell death by overexpression of ORP150 also was accompanied by the suppression of intracellular Ca++ elevation and proteolytic activity induced by excitatory amino acid. Further, overexpression of ORP150 in hippocampus by an adenovirus suppressed delayed
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neuronal death after transient ischemia in gerbils. (J Cereb Blood Flow Metab, 22 : 979-87,2002). These findings indicate that ER is a target of the stress inducing neuronal cell death.
Next, whether ER stress may occur in SN in the mouse model of Parkinson's disease induced by MDTP was examined. Tyrosine hydroxylase (TH)-positive neurons in SN are reduced in number by 50% after administration of MPTP for 5 days (30 mg/kg/day). These cells expressed ORP150 strongly, suggesting the degeneration of SN cells in association with the ER stress, Immunocytochemistry for TH and apoptotic markers and measuring dopamine concentration in the striatum revealed that the neurodegeneration were accelerated in ORP150 -/+ mice and were delayed in TG mice after MPTP treatment (in preparation). These results suggested that the degeneration induced by MTPT was accompanied by cell death originated from ER as well as mitochondria. The study suggests that decreasing ER-stress is one of the strategies for the treatment of Parkinson's disease. Less
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