| Project/Area Number |
20K17491
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Yamaguchi University |
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Principal Investigator |
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 卵巣老化 / アルドケト還元酵素 / ゲノム編集 / 性周期 / i-GONAD法 / RNA-seq / GONAD法 |
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| Outline of Research at the Start |
本研究では、 AKR1B7ノックアウトマウスにおける生殖機能の変化および卵巣老化の進行を詳細に解析し、AKR1B7の役割を解明する。AKR1B7が卵巣老化の進行に関与するのであれば、自然な卵巣老化から見出した原因分子として世界初の報告となる。ヒト卵巣寿命の延長に向けた分子基盤研究の扉を開く。
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| Outline of Final Research Achievements |
Through comprehensive gene expression analysis of mouse ovaries, we have found that aged ovaries show a significant decrease in aldoketoreductase 1B7 (AKR1B7) in the interstitial/theca cell layer as well as hCG response. Ovaries in AKR1B7-deficient young mice were analyzed to understand what kind of abnormalities occurred during hCG response. Aberrations in lipid synthesis were presumed from RNA-seq analysis, and a decrease in phospholipid content and AKT activity was actually observed. In addition, we observed decreased expression of the downstream gene of SF1, which has a phospholipid ligand, decreased downstream progesterone-metabolizing enzyme CYP17A1, increased blood levels of progesterone, and prolonged estrous cycle. As described above, an aberrations in lipid synthesis due to decreased AKR1B7 was involved in the progression of ovarian aging.
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣老化は妊娠能力低下を招くと同時に、卵巣ホルモン分泌異常により動脈硬化、骨粗しょう症、認知症といった加齢性疾患のリスク要因となる。その分子メカニズムを理解することは不妊治療にとって、さらに社会にとっても少子化緩和や健康寿命の増進を実現する上で重要である。本課題では老化卵巣で減少するアルドケト還元酵素1Bが、若い卵巣の脂質およびホルモン合成・代謝に関与していることが分かった。加齢に伴う月経周期や卵胞発育の異常を引き起こす因子の一つであることを示唆した。
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