2020 Fiscal Year Final Research Report
Regulatory mechanisms of aging of adult neural stem/progenitor cells via p38 MAPK
Project/Area Number |
18K06469
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 46010:Neuroscience-general-related
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Research Institution | Keio University |
Principal Investigator |
SHIMAZAKI Takuya 慶應義塾大学, 医学部(信濃町), 准教授 (00324749)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Keywords | 神経幹細胞 / 神経前駆細胞 / 神経新生 / p38 / 老化 / 増殖 / 成体脳 |
Outline of Final Research Achievements |
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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Free Research Field |
神経発生
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Academic Significance and Societal Importance of the Research Achievements |
これまで、成体脳における神経新生能の低下に関しては未解明な部分が多かった。p38 MAP-kinaseが成体脳神経新生に必要であり、加齢によるその発現低下が加齢に伴う神経新生能の低下の大きな要因であるという発見は、他の細胞増殖制御因子との関係を含めた成体NSPCsの老化機構の全容解明へ向けた突破口になるものである。さらに、p38の発現およびWntシグナルを制御することによる、老化によって可塑性が低下した脳の、NSPCsの動員による神経再生への期待を高める成果であるとも考えている。
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