2023 Fiscal Year Final Research Report
Comprehensive understanding and therapeutic application of developmental disorders caused by abnormal chromatin remodeling
| Project/Area Number |
21H02847
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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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| Review Section |
Basic Section 52030:Psychiatry-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | クロマチンリモデリング / 発達障害 |
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| Outline of Final Research Achievements |
We have now established Chd8 knock-in mice in order to characterize the effects of Chd8 duplication on transcriptional, neuroanatomical, and behavioral phenotypes. We found that Chd8 overexpression impairs the generation of deep-layer neurons in the brain. Transcriptomic analysis showed that Chd8 overexpression alters the expression of genes related to neural development and neuropsychiatric disease, and that the pattern of gene expression in the brain of Chd8 knock-in mice was negatively correlated with that apparent for Chd8 heterozygous mutant mice. Furthermore, behavioral analysis revealed that Chd8 overexpression results in hyperactivity and attenuated anxiety-like behavior, and that these behavioral changes were ameliorated by genetic or pharmacological interventions.
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| Free Research Field |
分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
神経発達障害には、自閉スペクトラム症（ASD）、注意欠陥・多動性障害（ADHD）、知的障害などさまざまな疾患が含まれ、遺伝的要素が強い複雑な病因が特徴である。ゲノムの特定領域の増減を伴うコピー数変異は、神経発達障害の根底にある主要な遺伝的要因である。欠失と重複の両方がこれらの病態に関与する個々の遺伝子座が数多く同定されており、適切な遺伝子量が神経発達と脳機能の重要な決定因子であることが示唆されているが、その根底にあるメカニズムは不明である。Chd8ノックインマウスはヒトのCHD8重複症候群のモデルマウスとして適しており、CHD8の発現増加が脳の発達と機能を変化させるメカニズムに光を当てた。
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