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KAKEN_18K06469seika.pdf
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:392.4 KB
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:May 17, 2022 |
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p38 MAPKを介した成体神経幹/前駆細胞老化制御機構の解明
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p38 MAPK オ カイシタ セイタイ シンケイカン/ゼンク サイボウ ロウカ セイギョ キコウ ノ カイメイ
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p38 MAPK o kaishita seitai shinkeikan/zenku saibō rōka seigyo kikō no kaimei
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Regulatory mechanisms of aging of adult neural stem/progenitor cells via p38 MAPK
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島崎, 琢也
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シマザキ, タクヤ
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Shimazaki, Takuya
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慶應義塾大学・医学部 (信濃町) ・准教授
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Research team head
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科研費研究者番号 : 00324749
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2021
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科学研究費補助金研究成果報告書
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2020
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哺乳類成体脳における神経新生は加齢とともに低下する。我々はp38 MAPキナーゼの加齢に伴う神経幹/前駆細胞(NSPCs)における発現低下が、その低下の大きな要因であることを発見した。NSPCsにおけるp38ファミリーの主アイソザイムであるp38alphaを欠損させると、幹細胞ではなく、前駆細胞(NPCs)の増殖が特異的に低下した一方、老化したNSPCsに強制発現させると、低下したNPCsの増殖と神経新生が回復した。また、p38はWntシグナルのアンタゴニストの発現抑制に必要であることも発見し、これらの遺伝子のノックダウンを老化マウスNSPCsで行うとNPCsの増殖が促進された。
Adult neurogenesis in mammalian brain declines with aging. We identify p38 MAP-Kinase as a key factor in the proliferation of neural progenitor cells (NPCs) but not stem cells in adult neurogenic niches. p38 expression in adult NSPCs is downregulated during aging. Deletion of p38alpha which is a major isozyme of p38 family in NSPCs reduces the proliferation of NPCs but not stem cells. Conversely, forced expression of p38alpha in NSPCs in the aged SVZ restores NPC proliferation and neurogenesis. We also found that p38 is necessary for suppressing the expression of Dickkopf-1(DKK1) and secreted frizzled-related protein 3(SFRP3) which are antagonists of the Wnt signaling. Moreover, the knockdown of either Dkk1 or Sfrp3 facilitates proliferation of NPCs in aged mouse SVZ. Age-related reduction in p38 thus leads to decreased adult neurogenesis via downregulation of Wnt signaling.
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研究種目 : 基盤研究 (C) (一般)
研究期間 : 2018～2020
課題番号 : 18K06469
研究分野 : 神経発生
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