| Project/Area Number |
18K19600
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Osuga Yutaka 東京大学, 医学部附属病院, 教授 (80260496)
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| Co-Investigator(Kenkyū-buntansha) |
廣田 泰 東京大学, 医学部附属病院, 講師 (40598653)
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
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| Keywords | p53 / Mdm2 / 卵巣 / 顆粒膜細胞 / 卵子成熟 / 排卵 / 受精 / SF1 / MDM2 / 不妊 / マウスモデル / 卵丘顆粒膜細胞 |
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| Outline of Final Research Achievements |
We investigated the functions of p53 and its suppressor Mdm2 in the ovary. Ovarian Mdm2-deficient mice become infertile due to impaired oocyte maturation, ovulation, and fertilization, and Mdm2/p53-deficient mice show normal fertility, suggesting that the induction of p53 adversely affects ovarian function. We found that an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function, is reduced by p53 induction in cumulus granulosa cells, and p53 regulates SF1 transcriptionally. The expression levels of MDM2 and SF1 in the human cumulus granulosa cells obtained from the in vitro fertilization patients were positively correlated with the oocyte maturation rate and the fertilization rate. These findings indicate that ovarian Mdm2-p53-SF1 axis controls oocyte quality, ovulation and fertilization.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究者らの過去の研究で子宮のp53低下・不活性化が着床障害や早産の原因になることがわかっていたが、本研究で卵巣おけるp53増加・活性化が卵子成熟不全や排卵障害を引き起こすことが明らかになり、生殖臓器の異なったp53の役割を見いだすことができた。個体が喫煙・肥満・化学療法・放射線療法などの外的ストレスに曝された場合、細胞はp53を活性化するため、卵巣のp53増加が直接的に卵子成熟不全や排卵異常を引き起こす可能性が考えられる。マウスモデルで得られた結果をヒト体外受精の臨床サンプルで確認できており、将来的な不妊治療への臨床応用への道筋をつけることができたという点で、社会的意義も大きい。
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