| Project/Area Number |
17390096
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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 | Kumamoto University |
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Principal Investigator |
ENDO Motoyoshi (2006) Kumamoto Univ., Dept. Mol. Genet., Grad. Sch. Med. Sci., Research Fellow, 大学院医学薬学研究部, 研究員 (40398243)
森 正敬 (2005) 熊本大学, 大学院・医学薬学研究部, 教授 (40009650)
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| Co-Investigator(Kenkyū-buntansha) |
GOTOH Tomomi Kumamoto Univ., Dept. Mol. Genet., Grad. Sch. Med. Sci., Lecturer, 大学院医学薬学研究部, 講師 (20264286)
遠藤 元誉 熊本大学, 大学院・医学薬学研究部, 技術支援者 (40398243)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2006: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Keywords | ER stress / CHOP / IL-1β / caspase-11 / inflammation / glutamic acid / neuronal cell death / neurotrophic factor / アポトーシス / LPS / XBP-1 / BiP / 骨髄腫 |
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| Research Abstract |
Endoplasmic reticulum (ER) stress pathway is activated by various stresses to protect ER functions. However, when stresses are severe, apoptosis is induced. Therefore, ER stress pathway is involved in the pathogenesis of various diseases. However, the precise molecular mechanisms of the ER stress-related diseases are still unknown. CHOP, a transcription factor of C/EBP family, is involved in ER stress-mediated apoptosis. In this study, we found that ER stress-CHOP pathway is involved in LPS-induced pneumonia and the neurotrophic factor deprivation-induced neuronal cell death.
LPS-induced inflammatory changes in lung were suppressed in Chop knockout mice. We found that the pro-IL-1/3 activation process is CHOP-dependent. Therefore, we conclude that ER stress-CHOP pathway regulates inflammatory processes through regulation of cytokines secretion.
Recently it was shown that neuronal stem cells still exist in brain even after birth. It is speculated that the number of neurons is regulated by
… More
the competition for the limited amount of neurotrophic factors. We found that the deprivation of neurotrophic factor activates ER stress-CHOP-apoptosis pathway, and this apoptosis was suppressed in CHOP knockout mice derived primary cultured neuronal cells. In addition, we showed that the subventricular zone, in which neuronal stem cells exist even after birth, is enlarged in CHOP knockout mice, probably because of the prevention of CHOP-induced neuronal apoptosis. Therefore, we conclude that ER stress-CHOP pathway is involved in the regulation of the number of neurons in adult brain. ER stress-CHOP pathway can be the new target of theraphy for ER stress-related diseases. However, the precise mechanisms how ER stress pathway is activated by inflammatory stimulus or neurotrophic factor-deprivation still remains to be elucidated. The signal transduction pathways downstream of CHOP are also not fully clarified. We are now investigating the precise molecular mechanisms of CHOP-induced apoptosis. Less
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