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Establishment of methods to upregulate the number of primordial follicles by activation of autophagy to improve lifelong fertility in mammals

Research Project

Project/Area Number 17K19316
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Veterinary medical science, Animal science, and related fields
Research InstitutionYamagata University

Principal Investigator

Kimura Naoko  山形大学, 農学部, 教授 (70361277)

Project Period (FY) 2017-06-30 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Keywords原始卵胞 / オートファジー / 新生仔 / 卵巣 / 生殖能 / 生殖寿命 / 卵母細胞
Outline of Final Research Achievements

In mice that received Tat-beclin 1 or Sulfasalazine by 54 h after birth, the primordial follicle numbers were increased by about 1.2 times, 1.1 times, respectively compared with the control group at 60 h. Especially in the 13 to 15 months old mice, the numbers of primordial follicles, the secondary follicles and graafian follicles in the Tat-bec.1 group were also significantly greater than that in the control group. The lifetime total number of offspring in the Tat-bec.1 group was at least 5 pups greater than that in control group, suggesting that the upregulated primordial follicles have a normal developmental potential.
We report that an enhancement in autophagy in neonatal mice during the follicle formation period accelerates follicle assembly by promoting oocyte survival. Consequently, the stockpile of primordial follicles expands, leading to an improvement in individual lifelong fertility. This approach could be effective in increasing reproductive ability in other animal species.

Academic Significance and Societal Importance of the Research Achievements

胎生後期から新生仔初期の卵巣で進行する原始卵胞形成過程の分子機構は、解析手法の難しさや動物モデルが少ないなどから、十分な全容解明には至っていない。本研究の原始卵胞数の上方制御モデルでの解析から、小サイズシストの優勢卵母細胞数が増加することで、卵の生存性が向上し、原始卵胞数の増加に寄与することが示唆された点は、学術的意義と考えられた。
また新生仔期に、安全性が高いオートファジー誘導剤の投与により、生体レベルで原始卵胞数を上方制御することで、生涯生殖能の向上に繋がることを実証できた点は、産業動物や希少な雌動物資源の維持と増産の効率化を図る上で、根本的解決に繋がり得る成果と考えられた。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (35 results)

All 2020 2019 2018 2017 Other

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (27 results) (of which Int'l Joint Research: 7 results,  Invited: 2 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Activation of autophagy in early neonatal mice increases primordial follicle number and improves lifelong fertility2020

    • Author(s)
      Watanabe R, Sasaki S, Kimura N
    • Journal Title

      Biology of Reproduction

      Volume: 102 Issue: 2 Pages: 399-411

    • DOI

      10.1093/biolre/ioz179

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ascorbic acid and CoQ10 ameliorate the reproductive ability of superoxide dismutase 1-deficient female mice†2019

    • Author(s)
      Ishii Naoki、Homma Takujiro、Lee Jaeyong、Mitsuhashi Hikaru、Yamada Ken-ichi、Kimura Naoko、Yamamoto Yorihiro、Fujii Junichi
    • Journal Title

      Biology of Reproduction

      Volume: 102 Pages: 102-115

    • DOI

      10.1093/biolre/ioz149

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A heterozygous deficiency in protein phosphatase Ppm1b results in an altered ovulation number in mice2019

    • Author(s)
      Ishii Naoki、Homma Takujiro、Watanabe Ren、Kimura Naoko、Ohnishi Motoko、Kobayashi Takayasu、Fujii Junichi
    • Journal Title

      Molecular Medicine Reports

      Volume: 19 Pages: 5353-5360

    • DOI

      10.3892/mmr.2019.10194

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A heterozygous deficiency in protein phosphatase Ppm1b results in an altered ovulation number in mice2019

    • Author(s)
      Ishii N, Homma T, Watanabe R, Kimura N, Ohnishi M, Komayashi T and Fujii J
    • Journal Title

      MOLECULAR MEDICINE REPORTS

      Volume: 印刷中

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Non-suckling starvation of neonatal mice promotes primordial follicle formation with activation of ovarian autophagy2018

    • Author(s)
      Watanabe R, Kimura N
    • Journal Title

      Journal of Reproduction and Development

      Volume: 64 Issue: 1 Pages: 89-94

    • DOI

      10.1262/jrd.2017-126

    • NAID

      130006405010

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decreased reproductive performance in xCT-knockout male mice.2017

    • Author(s)
      Hamashima S, Homma T, Kobayashi S, Ishii N, Kurahashi T, Watanabe R, Kimura N, Sato H, Fujii J.
    • Journal Title

      Free Radic Res.

      Volume: 51 Pages: 851-860

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 新生仔雌マウスへのオートファジー促進による原始卵胞数増加機構の解明と卵巣培養系での効果.2019

    • Author(s)
      佐々木将, 八木橋美里, 梅野拳, 小原瑞歩, 木村直子.
    • Organizer
      第57回東北生殖医学会総会・学術講演会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] Autophagy activation increase primordial follicle number with raising oocyte viability.2019

    • Author(s)
      Sasaki S, Obara M, Umeno K, Watanabe R, Kimura N.
    • Organizer
      14th World Congress of the International Society for Immunology of Reproduction
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マウスへの複合的な慢性ストレス条件の構築と雌生殖能への影響.2019

    • Author(s)
      横田 裕也・小原 瑞歩・木村 直子.
    • Organizer
      日本畜産学会126回大会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] マウスの原始卵胞形成過程におけるTNF-αの関与.2019

    • Author(s)
      梅野 拳,木村 直子.
    • Organizer
      第112回日本繁殖生物学会大会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] マウスの原始卵胞形成過程におけるコルチゾール経路の関与.2019

    • Author(s)
      小原 瑞歩,梅野 拳,佐々木 将,木村 直子.
    • Organizer
      第112回日本繁殖生物学会大会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新生仔マウスのオートファジーの活性化はシスト内卵母細胞の集約を促進し原始卵胞形成を促す.2019

    • Author(s)
      佐々木将, 小原瑞歩, 梅野拳, 渡辺連, 木村直子.
    • Organizer
      第69回東北畜産学会大会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新生仔マウス卵巣の培養におけるオートファジー誘導剤添加の検討.2019

    • Author(s)
      八木橋美里, 佐々木将, 渡辺連, 木村直子.
    • Organizer
      第69回東北畜産学会大会. 2019年8月28日.
    • Related Report
      2019 Annual Research Report
  • [Presentation] 哺乳類卵の酸化障害と老化~低減する添加剤の検討.2019

    • Author(s)
      木村直子.
    • Organizer
      第34回平成不妊研究会.
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] マウス新生仔期のオートファジー活性化による原始卵胞数増加メカニズムの解明.2019

    • Author(s)
      佐々木将, 梅野拳, 小原瑞歩, 渡辺連, 木村直子.
    • Organizer
      第60回日本卵子学会学術集会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] xCT遺伝子欠損雌マウスの高い卵胞備蓄能とxCT阻害剤の投与による卵胞数制御の試み2018

    • Author(s)
      渡辺連, 佐藤英世, 木村直子
    • Organizer
      日本卵子学会第59回学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 新生仔期のオートファジーの誘導は原始卵胞の形成を促進し卵巣予備能を高める2018

    • Author(s)
      渡辺連, 佐々木将, 木村直子
    • Organizer
      第36回日本受精着床学会総会・学術講演会
    • Related Report
      2018 Research-status Report
  • [Presentation] High ovarian reserve in cystine-glutamate transporter gene deficient mice.2018

    • Author(s)
      Ren Watanabe, Hideyo Sato, Naoko Kimura
    • Organizer
      51th Annual Meeting of the Society for the Study of Reproduction
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 新生仔マウスのオートファジーの促進は原始卵胞プールを拡大し生殖能を高める2018

    • Author(s)
      渡辺連, 佐々木将, 木村直子
    • Organizer
      第111回日本繁殖生物学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 新生仔マウスにおける卵母細胞シストの形態学的評価2018

    • Author(s)
      佐々木将, 渡辺連, 木村直子
    • Organizer
      第111回日本繁殖生物学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] マウス初期胚の発生能に及ぼす培地へのmi RNA阻害剤添加の影響2018

    • Author(s)
      宮島理央, 横田裕也, 小原瑞歩, 木村直子
    • Organizer
      第111回日本繁殖生物学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 哺乳類雌の生殖寿命延伸に向けたアプローチ:原始卵胞プールの上方制御と老齢個体卵のレスキュー培養2018

    • Author(s)
      木村直子
    • Organizer
      第33回日本生殖免疫学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 新生仔期卵巣内のオートファジー活性化による原始卵胞形成過程の形態学的解析2018

    • Author(s)
      佐々木将, 渡辺連, 小原瑞歩, 木村直子
    • Organizer
      第33回日本生殖免疫学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] PP1の発現動態を指標とする染色体異数性発生機序の解析および異数性低減培養系の検討2017

    • Author(s)
      鈴木瑞穂,小原太樹,藤井順逸,木村直子
    • Organizer
      第58回日本卵子学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] マウス卵の紡錘体形態に及ぼす加齢あるいは酸化ストレス の影響の違いの検証2017

    • Author(s)
      石井実佳,石塚美咲,藤井順逸,木村直子
    • Organizer
      第58回日本卵子学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Starvation and exogenous autophagy inducer increases the number of primordial follicles at neonatal period.2017

    • Author(s)
      Ren Watanabe, Naoko Kimura
    • Organizer
      50th Annual Meeting of the Society for the Study of Reproduction
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 卵初期発生過程におけるグルクロン酸抱合機構の解 明と高発生能培地への応用~アルデヒド還元酵素遺伝子欠損マウス卵の解析から~2017

    • Author(s)
      岡部友香,高橋素子,宮田哲,藤井順逸,木村直子
    • Organizer
      第35回日本受精着床学会総会・学術講演会
    • Related Report
      2017 Research-status Report
  • [Presentation] SAC因子Mps1の発現動態を指標とした酸化ストレスによる染 色体異数性発生機序の解明2017

    • Author(s)
      小原太樹,鈴木瑞穂,藤井順逸,木村直子
    • Organizer
      第35回日本受精着床学会総会・学術講演会
    • Related Report
      2017 Research-status Report
  • [Presentation] Starvation and exogenous autophagy inducer increases the number of primordial follicles at neonatal period.2017

    • Author(s)
      Ren Watanabe, Naoko Kimura
    • Organizer
      4th World Congress of Reproductive Biology.
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effect on N-acetyl-L-cyctein for chromosome aneuploidy of oocytes from SOD1 deficient mice.2017

    • Author(s)
      Mizuho Suzuki, Taiki Ohara, Junichi Fujii, Naoko Kimura
    • Organizer
      4th World Congress of Reproductive Biology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Glucuronidation in involved with early embryonic development in vitro.2017

    • Author(s)
      Yuka Okabe, Motoko Takahashi, Satoshi Miyata, Junichi Fujii, Naoko Kimura
    • Organizer
      4th World Congress of Reproductive Biology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effect on NAD+ precursor in aged mice oocytes matured in vitro on spindle morphology and developmental ability.2017

    • Author(s)
      Mika Ishii, Misaki Ishizuka, Mizuho Suzuki, Naoko Kimura
    • Organizer
      4th World Congress of Reproductive Biology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] xCT遺伝子欠損雌マウスの高い備蓄卵胞数の要因解明とそれらを利用した卵胞数制御の試み2017

    • Author(s)
      渡辺連, 佐藤英世, 木村直子
    • Organizer
      日本畜産学会第124回大会
    • Related Report
      2017 Research-status Report
  • [Book] BIO Clinica2018

    • Author(s)
      渡辺連、佐々木将、木村直子
    • Total Pages
      3
    • Publisher
      北隆館
    • Related Report
      2018 Research-status Report
  • [Remarks] 山形大学農学部動物機能調節学分野紹介(トピックスおよび研究業績のページに記載)

    • URL

      https://www.tr.yamagata-u.ac.jp/~animal-reprod./

    • Related Report
      2018 Research-status Report

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Published: 2017-07-21   Modified: 2021-02-19  

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