| Project/Area Number |
15K06694
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurophysiology / General neuroscience
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| Research Institution | Institute for Developmental Research, Aichi Human Service Center (2017-2018)
Tohoku University (2015-2016) |
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Principal Investigator |
Yoshizaki Kaichi 愛知県心身障害者コロニー発達障害研究所, 病理学部, 研究員 (50393161)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 次世代エピゲノム継承 / 父親の高齢化 / 精子DNAメチル化 / 行動薬理学 / 超音波発声 / 言語コミュニケーション障害 / REST/NRSF / 神経発生 / GSEA解析 |
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| Outline of Final Research Achievements |
Comprehensive DNA methylome analyses revealed that DNA hypo-methylation in sperm from aged father. Intriguingly, DNA hypo-methylation frequently contains REST/NRSF binding motif rather than random. Similarly, comprehensive gene expression analyses also found that REST/NRSF target genes expression was significantly altered. Offspring derived from mice injected DNA methyltransferase inhibitor exhibited behavioral abnormalities which was similar to that in offspring derived from aged father. These suggest that DNA hypo-methylation in sperm from aged father impact behavioral abnormalities in subsequent generation, in which REST/NRST is a candidate gene linked between paternal aging and neuronal development in offspring.
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| Academic Significance and Societal Importance of the Research Achievements |
父親の高齢化はその子供に対して様々な疾患リスクを増大させることが報告されており、その分子病態としてDNA複製エラーに伴う精子のDNA変異が想定されてきた。本研究では、新たな可能性として加齢に伴う精子のDNAメチル化異常が疾患リスクを引き起こすことを見出した。さらに興味深いことに、高齢の父親マウスの精子および仔マウス脳に共通して転写因子REST/NRSFが中核的な役割を担うことを明らかにした。
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