| Project/Area Number |
23300138
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Tokyo Metropolitan Institute of Medical Science |
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Principal Investigator |
NAMEKATA Kazuhiko 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 副参事研究員 (70392355)
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| Co-Investigator(Renkei-kenkyūsha) |
GUO Xiaoli 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 主任研究員 (50443114)
KIMURA Atsuko 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 主任研究員 (60569143)
WATANABE Hayaki 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 研究員 (70595587)
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| Project Period (FY) |
2011-04-01 – 2014-03-31
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000)
Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
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| Keywords | Dock3 / 緑内障 / 神経保護 / 神経変性疾患 / 視神経再生 / Dockファミリー / 細胞死 / アクチン / 微小管 / アルツハイマー病 / 多発性硬化症 / 軸索再生 / アクチン骨格 / GEF |
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| Research Abstract |
Dock3 is a guanine nucleotide exchange factors for the small GTPase Rac1. We found that Dock3 directly binds to NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress.
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