Sex steroid hormones function in sex-related psychiatric disease
| Project/Area Number |
17K07137
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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 |
Laboratory animal science
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| Research Institution | The University of Tokushima |
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Principal Investigator |
MATSUMOTO Takahiro 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (70447374)
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| Co-Investigator(Kenkyū-buntansha) |
岡村 永一 滋賀医科大学, 動物生命科学研究センター, 助教 (30755913)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 男性ホルモン / 精神疾患 / 気分障害 / 性ホルモン / うつ |
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| Outline of Final Research Achievements |
We have previously found that AR, ERa and ERb knockout (TKO) males display increased anxiety-related behavior, owing to the decreased levels of postsynaptic 5-HT1A receptor in the cortex and hippocampus. However, the molecular basis for the transcriptional and epigenomic regulation of the 5-HT1A receptor gene remains unclear. We reported here that DEAF1 binds to specific sequence in proximal region of the 5-HT1A receptor gene promoter, and transactivates 5-HT1A receptor expression. This transcriptional regulation required methylated histone H3 K4 prior to DEAF1 association with chromatin. Furthermore, AR/ERa and ERb binding regions of DEAF1 gene was mapped to the minimal promoter sites and 5’-untranslated region (5’-UTR). Finally, we generated Deaf1 knockout mice via a CRISPR/Cas9 system and revealed that disruption of Deaf1 in mice results in neural tube defects and is neonatal lethal.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、アンドロゲンの抗うつ作用は、アンドロゲン依存的なヒストンH３K４のジメチル及びトリメチル化修飾を介したDEAF1によるセロトニン1A受容体の転写調節の一旦を担うことが明らかとなった。今回の研究により、性ホルモンとヒストン修飾の機能相関が示唆されたことは、今後の精神疾患研究においても意義は大きいものと考える。今後は、アンドロゲン依存性気分障害モデルマウスを用い、抗うつ薬剤の開発を行う際、本研究により同定された標的遺伝子やヒストン修飾を指標としたスクリーニングが有効となるか、さらなる検証を進めていく必要がある。
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Report
(4 results)
Research Products
(2 results)
