神経投射再生を目指した評価系の構築とそれを制御する低分子化合物の探索
Project/Area Number |
21650089
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Single-year Grants |
Research Field |
Neurochemistry/Neuropharmacology
|
Research Institution | Kyoto University |
Principal Investigator |
赤池 昭紀 京都大学, 薬学研究科, 教授 (80135558)
|
Co-Investigator(Kenkyū-buntansha) |
久米 利明 京都大学, 薬学研究科, 准教授 (10303843)
泉 安彦 京都大学, 薬学研究科, 助教 (60456837)
|
Project Period (FY) |
2009 – 2010
|
Project Status |
Completed (Fiscal Year 2010)
|
Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2010: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2009: ¥1,600,000 (Direct Cost: ¥1,600,000)
|
Keywords | 神経投射 / 神経突起伸長 / ドパミンニューロン / インテグリン / 神経再生 / 神経幹細胞 |
Research Abstract |
パーキンソン病は、中脳黒質ドパミンニューロンの選択的脱落を病理学的特徴とし、その投射先である線条体でのドパミン量の低下に起因する運動機能障害を呈する神経変性疾患である。本研究では、パーキンソン病で失われた黒質-線条体神経投射を再生させるために、まず、ドパミンニューロンによる線条体神経支配の機序を明らかにすることを目指した。はじめに、中脳初代分散培養細胞を用いてドパミンニューロンによる線条体神経支配を評価できる系の構築を試みた。シリコン製隔離壁を用いて中脳細胞領域と線条体細胞領域を対峙させて形成し、培養したところ、ドパミンニューロンの軸索は中脳細胞領域から線条体細胞領域へ著しく進展した。進展したドパミンニューロンの軸索は線条体ニューロンとシナプスを形成していたことから、神経支配が成立していると考えられた。次に、ドパミンニューロンによる線条体神経支配の機序を検討したところ、液性因子の関与は小さく、細胞接着因子であるインテグリンの寄与が大きいことを明らかとなった。インテグリンはαとβのサブユニットからなるヘテロダイマーで、そのサブタイプについて特定したところ、インテグリンα5β1が重要な役割を果たしていることを見出した。この新知見は黒質-線条体ドパミン神経投射の形成機構の一端を解明しただけでなく、ドパミンニューロンによる線条体神経支配を促進する分子を見出したという点で、パーキンソン病における細胞移植療法の実用化に大いに貢献すると考えられる。
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Report
(2 results)
Research Products
(76 results)
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[Journal Article] Glutathione biosynthesis via activation of the nuclear factor E2-related factor 2(Nrf2)-antioxidant-response element (ARE) pathway is essential for neuroprotective effects of sulforaphane and 6-(methylsulfinyl) hexyl isothiocyanate.2011
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Takahashi, J., Hijikuro, I., Kihara, T., Murugesh, G.M., Fuse, S., Tsumura, Y., Akaike, A., Niidome, T., Takahashi, T., Sugimoto, H.
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Pages: 1721-1723
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[Journal Article] Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection.2010
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Yamamoto, N., Izumi, Y., Matsuo, T., Wakita, S., Kume, T., Takada-Takatori, Y., Sawada, H., Akaike, A.
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Volume: 88
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[Journal Article] Depolarizing stimuli cause persistent and selective loss of orexin in rat hypothalamic slice culture.2010
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Matsuo, T., Izumi, Y., Wakita, S., Kume, T., Takada-Takatori, Y., Sawada, H., Akaike, A.
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Volume: 640
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[Journal Article] Mitogen-activated protein kinases support survival of activated microglia that mediate thrombin-induced striatal injury in organotypic slice culture.2010
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Ohnishi, M., Katsuki, H., Izumi, Y., Kume, T., Takada-Takatori, Y., Akaike, A.
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Volume: 88
Pages: 2155-2164
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[Journal Article] Heme oxygenase-1 contributes to pathology associated with thrombin-induced striatal and cortical injury in organotypic slice culture.2010
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Journal Title
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Volume: 1347
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[Journal Article] Protective effect of aripiprazole against glutamate cytotoxicity in dopaminergic neurons of rat mesencephalic cultures.2010
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Matsuo, T., Izumi, Y., Kume, T., Takada-Takatori, Y., Sawada, H., Akaike, A.
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Volume: 481
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Volume: 192
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[Journal Article] Serofendic acid promotes stellation induced by cAMP and cGMP analogs in cultured cortical astrocytes2009
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[Journal Article] Serofendic acid protects from iodinated contrast medium and high glucose probably against superoxide production in LLC-PK1 cells2009
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Journal Title
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[Presentation] Paraquat activates Nrf2-ARE pathway : implication of decrease in proteasome activity in dopamine-mediated cytotoxicity.2010
Author(s)
Izumi, Y., Matsushima, S., Yamamoto, N., Kume, T., Sawada, H., Akaike, A.
Organizer
World Pharma 2010
Place of Presentation
Copenhagen, Denmark
Year and Date
2010-06-19
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[Presentation] Reconstruction of the nigrostriatal projections in dissociated primary cultures : A role of striatal cells in dopaminergic neurite outgrowth.2010
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Wakita, S., Izumi, Y., Kume, T., Sawada, H., Akike, A.
Organizer
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Place of Presentation
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Year and Date
2010-06-19
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[Book] 薬物動態学2010
Author(s)
柴崎正勝、赤池昭紀、橋田充, 他10名
Total Pages
196
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