Elucidation of neurodevelopmental disorder caused by CaMK2 mutant mice
Project/Area Number |
20K07423
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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 49030:Experimental pathology-related
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Research Institution | Hamamatsu University School of Medicine |
Principal Investigator |
Mutoh Hiroki 浜松医科大学, 医学部, 助教 (60443040)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | CaMK2β / ヒト疾患モデル動物 / 脳波異常 / 興奮性/抑制性のバランス / 神経発達異常 / 疾患モデル動物 |
Outline of Research at the Start |
小児期難治性てんかん患者の遺伝子解析により、CaMK2βの自己抑制ドメイン異常がてんかんなど神経発達障害の原因になり得ることが分かった。興味深いことに、患者と相同な変異を導入したCaMK2β変異ノックインマウスは、定常状態でガンマ帯域に異様な増強を示す顕著な脳波異常が示した。そこで、本申請では、CaMK2β変異ノックインマウスで生じる脳波異常と興奮性/抑制性バランス異常の関係性を明らかにすることで、神経発達障害モデルマウスの確立と神経回路形成におけるCaMK2βの役割を解明する。
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Outline of Final Research Achievements |
Mouse models of human disease in which CaMK2β mutations were introduced, identified from patients with neurodevelopmental disorders, showed motor dysfunction and growth retardation similar to patients, and a remarkably decreased expression level of CaMK2β protein in the cerebellum. Furthermore, in the model mice, even a slight decrease in protein expression in the cerebral cortex and hippocampus was found to disrupt the excitatory/inhibitory balance of the neuronal circuitry and produce abnormal EEG. The disruption of the excitatory-inhibitory balance was also found to increase susceptibility to epilepsy. This study successfully established a mouse model of human disease in which CaMK2β mutations were introduced.
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Academic Significance and Societal Importance of the Research Achievements |
本研究課題の成果により、CaMK2βが神経回路形成における興奮性・抑制性のバランス制御に必要である学術的に重要な発見をした。また、難治性神経疾患の患者より同定した変異を導入したヒト疾患モデルマウスの作出、機能解析することで病態の一端を解明することにも成功し、難治性疾患の病態解明と新たな薬剤開発や治療法につながることが期待される。
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Report
(4 results)
Research Products
(8 results)
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[Journal Article] ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice2021
Author(s)
Aoto K, Kato M, Akita T, Nakashima M, Mutoh H, Akasaka N, Tohyama J, Nomura Y, Hoshino K, Ago Y, Tanaka R, Epstein O, Ben-Haim R, Heyman E, Miyazaki T, Belal H, Takabayashi S, Ohba C, Takata A, Mizuguchi T, Miyatake S, Miyake N, Fukuda A, Matsumoto N and Saitsu H
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Journal Title
Nat Commun
Volume: 12
Issue: 1
Pages: 2107-2107
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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