Elucidation of folliculogenesis by spatio-temporal investigation

• Project/Area Number: 15H04984
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Nagoya University
• Principal Investigator: Iwase Akira 名古屋大学, 医学部附属病院, 病院教授 (20362246)
• Co-Investigator(Kenkyū-buntansha): 後藤 真紀 名古屋大学, 医学部附属病院, 病院講師 (90378125) ; 滝川 幸子 名古屋大学, 医学部附属病院, 病院講師 (70456664) ; 中村 智子 名古屋大学, 医学部附属病院, 助教 (40732681) ; 中原 辰夫 名古屋大学, 医学部附属病院, 助教 (50534830)
• Co-Investigator(Renkei-kenkyūsha): MURASE Tomohiko 名古屋大学, 医学部附属病院, 助教 (90803114)
• Research Collaborator: WEI wei 名古屋大学, 大学院医学系研究科, 大学院生 ; NGUYEN Phuoc Xuan 名古屋大学, 大学院医学系研究科, 大学院生 ; KOMATSU Kouji 愛知医科大学, 生理学Ⅰ講座, 講師
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2015: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: 生殖医学 / 卵巣 / 卵胞発育 / 体外培養 / タイムラプス / 卵巣組織培養

Outline of Final Research Achievements

The purpose of our project was to analyze the mechanism of early follicle development and consequently develop new drugs for ovarian stimulation and ex vivo ovarian tissue culture system.
We established visualized murine ovarian tissue culture system and identified GDF-9, bFGF and IGF-1 as a stimulating factor and AMH as an inhibiting factor for follicle development. We also identified kisspeptin and phonexin as a novel peptide factor inducing follicle development.
We demonstrated that the factors mentioned above induced follicle development in ex vivo murine ovarian tissue culture and efficiently produced matured oocytes. However, the investigation using human ovarian tissues revealed that ex vivo-induction of follicle development was not feasible because of the differences in ovarian sizes and follicle growth cycles.

Research Products

• [Int'l Joint Research] カリフォルニア大学サンディエゴ校(米国)
• [Journal Article] Follicle dynamics: visualization and analysis of follicle growth and maturation using murine ovarian tissue culture. (2018)
  • Author(s): Tomohiko Murase, Akira Iwase, Kouji Komatsu, Tomoko Nakamura, Satoko Osuka, Sachiko Takikawa, Maki Goto, Tomomi Kotani, Fumitaka Kikkawa
  • Journal Title: Journal of Assisted Reproduction and Genetics Volume: 35 Issue: 2 Pages: 339-343
  • DOI: 10.1007/s10815-017-1073-5
  • Peer Reviewed / Open Access
• [Journal Article] FOXL2C134W-induced CYP19 expression via cooperation with SMAD3 in HGrC1 cells. (2018)
  • Author(s): Martina Belli, Nahoko Iwata, Tomoko Nakamura, Akira Iwase, Dwayne G Stupack, Shunichi Shimasaki
  • Journal Title: Endocrinology Volume: 159 Issue: 4 Pages: 1690-1703
  • DOI: 10.1210/en.2017-03207
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PAI-1 in granulosa cells is suppressed directly by statin and indirectly by suppressing TGF-β and TNF-α in mononuclear cells by insulin-sensitizing drugs. (2017)
  • Author(s): Yamada-Nomoto K, Yoshino O, Akiyama I, Iwase A, Ono Y, Nakamura T, Harada M, Nakashima A, Shima T, Ushijima A, Osuga Y, Chang RJ, Shimasaki S, Saito S.
  • Journal Title: Am J Reprod Immunol. Volume: 78 Issue: 1 Pages: 1-8
  • DOI: 10.1111/aji.12669
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Exogenous GDF-9 Treatment Induces Follicular Development Through Downregulation of Anti-Mullerian Hormone Receptor as Visualized in the Sliced Ovarian Tissue Culture System (2018)
  • Author(s): Tomohiko Murase, Akira Iwase, Kouji Komatsu, Wei Wei, Umida Ganieva, Bayasula, Ying Qin, Phuoc Xuan Nguyen, Sayako Yoshita, Ayako Muraoka, Shotaro Hayashi, Yukiyo Kasahara, Natsuki Nakanishi, Takashi Nagai, Ken Shimizu, Chiharu Ishida, Tomoko Nakamura, Satoko Osuka, Maki Goto, Fumitaka Kikkawa
  • Organizer: 65th Society for Reproductive Investigation Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] Directive Action of Neuropeptide Phoenixin and Its Receptor GPR173 during Folliculogenesis (2018)
  • Author(s): Phuoc Xuan Nguyen, Akira Iwase, Tomohiko Murase, Umida Ganieva, Ying Qin, Bayasula, Ken Shimizu, Satoko Osuka, Tomoko Nakamura, Maki Goto, Fumitaka Kikkawa
  • Organizer: 65th Society for Reproductive Investigation Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] Growth Differentiation Factor 9 induces Granulosa Cell Proliferation via Inhibition of the Expression of AMH Type II Receptor. (2017)
  • Author(s): Akira Iwase, Satoko Osuka, Bayasula, Sachiko Takikawa, Tomohiko Murase, Tomoko Nakamura, Maki Goto, Fumitaka Kikkawa
  • Organizer: 64th Society for Reproductive Investigation Annual Scientific Meeting
  • Place of Presentation: オーランド（アメリカ）
  • Year and Date: 2017-03-15
• [Presentation] Analysis of Follicular Growth and Oocyte Maturation in Cultured Murine Ovarian Tissue. (2017)
  • Author(s): Tomohiko Murase, Akira Iwase, Phuoc Xuan Nguyen, Umida Ganieva, Ying Qin, Natsuki Nakanishi, Yukiyo Kasahara, Takashi Nagai, Ken Shimizu, Chiharu Ishida, Nao Kato, Satoko Osuka, Tomoko Nakamura, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa
  • Organizer: 64th Society for Reproductive Investigation Annual Scientific Meeting
  • Place of Presentation: オーランド（アメリカ）
  • Year and Date: 2017-03-15
• [Presentation] 顆粒膜細胞におけるゴナドトロピンレセプターの発現制御 (2017)
  • Author(s): 清水顕、岩瀬明、仲西菜月、笠原幸代、永井孝、石田千晴、加藤奈緒、邨瀬智彦、大須賀智子、滝川幸子、後藤真紀、吉川史隆
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] 多嚢胞性卵巣症候群モデルラットにおけるエピジェネティック変異解析 (2017)
  • Author(s): 大須賀智子、岩瀬明、仲西菜月、永井孝、笠原幸代、清水顕、邨瀬智彦、加藤奈緒、石田千晴、滝川幸子、後藤真紀、吉川史隆
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] マウス卵巣組織培養による卵胞、卵母細胞の発育解析と顆粒膜細胞増殖の評価 (2017)
  • Author(s): 邨瀬智彦、岩瀬明、仲西菜月、笠原幸代、永井孝、清水顕、石田千晴、加藤奈緒、大須賀智子、滝川幸子、後藤真紀、吉川史隆
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] Epigenetic regulation of gonadotropin receptor expression in human granulosa cells. (2017)
  • Author(s): Ken Shimizu, Akira Iwase, Phuoc Xuan Nguyen, Ganieva Umida, Ying Qin, Bayasula, Natsuki Nakanishi, Takashi Nagai, Yukiyo Kasahara, Tomohiko Murase, Nao Kato, Chiharu Ishida, Satoko Osuka, Tomoko Nakamura, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Prevention of chemotherapy-induced ovarian damage by the superoxide dismutase mimetic activity of mangafodipir. (2017)
  • Author(s): Ying Qin, Akira Iwase, Bayasula, Tomohiko Murase, Satoko Osuka, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Phoenixin (PNX) and its novel receptor GPR173 in human ovary: Expression and regulation for steroidogenic enzymes. (2017)
  • Author(s): Phuoc Xuan Nguyen, Akira Iwase, Tomohiko Murase, Ganieva Umida, Ying Qin, Bayasula, Ken Shimizu, Satoko Osuka, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Exogenous growth differentiation factor-9 treatment induces follicle development through downregulation of anti-Müllrian hormone receptor as visualized in the sliced ovarian tissue culture system. (2017)
  • Author(s): Tomohiko Murase, Akira Iwase, Kouji Komatsu, Bayasula, Ying Qin, Phuoc Xuan Nguyen, Natsuki Nakanishi, Takashi Nagai, Ken Shimizu, Nao Kato, Satoko Osuka, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] Proteome analysis for ovarian autoimmunity in primary ovarian insufficiency (POI) patients. (2017)
  • Author(s): Satoko Osuka, Akira Iwase, Yukiyo Kasahara, Shotaro Hayashi, Phuoc Xuan Nguyen, Ying Qin, Takashi Nagai, Ken Shimizu, Bayasula, Tomohiko Murase, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa
  • Organizer: 4th World Congress of Reproductive Biology
  • Int'l Joint Research
• [Presentation] ヒト顆粒膜細胞においてBMP15 はp38 MAPK 経路を介してFSHR を誘導する (2017)
  • Author(s): 清水顕，岩瀬明，林祥太郎，村岡彩子，吉田沙矢子，仲西菜月，笠原幸代，永井孝，石田千晴，加藤奈緒，邨瀬智彦，大須賀智子，巴雅蘇拉，中村智子，滝川幸子，後藤真紀，吉川史隆
  • Organizer: 第62回日本生殖医学会学術講演会
• [Presentation] ヒト顆粒膜細胞におけるゴナドトロピンレセプターの発現制御 (2017)
  • Author(s): 清水顕、岩瀬明、Nguyen Xuan Phuoc、Ganieva Umida、Qin Ying、仲西菜月、笠原幸代、永井孝、邨瀬智彦、石田千晴、加藤奈緒、大須賀智子、中村智子、滝川幸子、後藤真紀、吉川史隆
  • Organizer: 第21回日本生殖内分泌学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
• [Presentation] マウス卵巣組織培養による卵胞発育解析とBrdU免疫染色法を用いた顆粒膜細胞増殖の評価 (2017)
  • Author(s): 邨瀬智彦、岩瀬明、Nguyen Xuan Phuoc、Ganieva Umida、Qin Ying、仲西菜月、笠原幸代、永井孝、清水顕、石田千晴、加藤奈緒、大須賀智子、中村智子、滝川幸子、後藤真紀、吉川史隆
  • Organizer: 第21回日本生殖内分泌学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
• [Presentation] マウス卵巣組織培養における卵胞発育解析とBrdU免疫染色法による顆粒膜増殖の評価 (2016)
  • Author(s): 邨瀬智彦、岩瀬明、仲西菜月、笠原幸代、清水顕、石田千晴、加藤奈緒、大須賀智子、中村智子、滝川幸子、後藤真紀、吉川史隆
  • Organizer: 第61回日本生殖医学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-03
• [Presentation] マウス卵巣組織培養における初期卵胞発育因子の検討 (2016)
  • Author(s): 邨瀬智彦, 加藤奈緒, 柵木善多, 笠原幸代, 永井孝, 清水顕, 大須賀智子, 中村智子, 滝川幸子, 後藤真紀, 岩瀬明, 吉川史隆
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-04-21
• [Presentation] Analysis of the Effect of Growth Factors on the Early Stages of Follicular Development in Cultured Murine Ovarian Tissue Through the Use of BrdU Immunostaining (2016)
  • Author(s): 邨瀬智彦、岩瀬 明
  • Organizer: 63rd Annual Scientific Meeting of Society of Reproductive Investigation
  • Place of Presentation: Montreal (Canada)
  • Year and Date: 2016-03-16
  • Int'l Joint Research