Evidence of the activation of unfolded protein response in granulosa and cumulus cells during follicular growth and maturation

• Project/Area Number: 24791689
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: HARADA Miyuki 東京大学, 医学部附属病院, 助教 (70451812)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 卵巣 / 小胞体ストレス / 卵胞発育 / 卵胞成熟 / 顆粒膜細胞 / 卵子成熟

Research Abstract

Follicular growth and maturation are known to be regulated by intra-ovarian factors, although the mechanisms are still to be known. Recently, unfolded protain response (UPR) has been known to have essential roles in keeping homeostasis. In the present study, to test whether UPR in granulosa cells (GC) and cumulus cells (CC) is involved in the process of follicular growth and maturation, we examined the presence of UPR in GC during follicular growth and the association between UPR expression in CC and oocyte maturity. UPR-related genes, spliced form of X-box binding protein -1 (XBP1(S)) and heat shock 70kDa protein 5 (HSPA5), were expressed in mice GC of growing follicels, and their expression is stage-dependent. In addition, the expression levels of XBP1(S) mRNA in CC enclosing human mature oocytes were 2-fold higher than those in CC enclosing immature ooytes. These findings suggest that UPR is activated in GC during follicular growth, playing roles in follicular growth and maturation.

Research Products

• [Journal Article] Bone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cells. (2014)
  • Author(s): Akiyama I, Yoshino O et al.
  • Journal Title: Reprod Sci. Volume: 21(4) Issue: 4 Pages: 477-82
  • DOI: 10.1177/1933719113503411
  • Peer Reviewed
• [Journal Article] Predictive factors for recurrence of mature cystic teratomas after surgical excision (2013)
  • Author(s): Harada M, Osuga Y, Fujimoto A, Fujimoto A, Yano T, Kozuma S
  • Journal Title: Eur J Obstet Gynecol Reprod Biol Volume: 171 Pages: 325-8
  • Peer Reviewed
• [Journal Article] The significance of serum anti-Mullerian hormone (AMH) levels in patients over age 40 in first IVF treatment. (2013)
  • Author(s): Tokura Y, Yoshino O, Ogura-Nose S, Motoyama H, Harada M, Osuga Y, Shmizu Y, Ohara M, Yorimitsu T, Nishii O, Kozuma S, Kawamura T.
  • Journal Title: J Assist Reprod Genet. Volume: 30 Issue: 6 Pages: 821-5
  • DOI: 10.1007/s10815-013-9991-3
  • Peer Reviewed
• [Journal Article] Interleukin-4 and prostaglandin E2 synergistically up-regulate 3β-hydroxysteroid dehydrogenase type 2 in endometrioma stromal cells (2013)
  • Author(s): Urata Y, Osuga Y, Akiyama I, Nagai M, Izumi G, Takamura M, Hasegawa A, Harada M, Hirata T, Hirota Y, Yoshino O, Koga K, Kozuma S
  • Journal Title: J Clin Endocrinol Metab Volume: 98(4) Issue: 4 Pages: 1583-90
  • DOI: 10.1210/jc.2012-3475
  • Peer Reviewed
• [Journal Article] Cyclic Stretch Augments Production of Neutrophil Chemokines and Matrix Metalloproteinases-1 (MMP-1) from Human Decidual Cells, and the Production was Reduced by Progesterone. (2013)
  • Author(s): Zhao Y, Koga K, Osuga Y, Izumi G, Takamura M, Harada M, Hirata T, Hirota Y, Yoshino O, Inoue S, Fujii T, Kozuma S
  • Journal Title: Am J Reprod Immunol Volume: 69 Issue: 5 Pages: 454-462
  • DOI: 10.1111/aji.12092
  • Peer Reviewed
• [Journal Article] 採卵数の少ない症例に ICSI は必要か (2013)
  • Author(s): 大井なぎさ, 原田美由紀, 藤本晃久, 大須賀穣
  • Journal Title: 産婦人科の実際 Volume: 62 Pages: 1279-84
  • NAID: 40019806404
• [Journal Article] 累積妊娠率から見た至適採卵数の検討 (2013)
  • Author(s): 大井なぎさ, 原田美由紀, 藤本晃久, 大石元, 平田哲也, 堤亮, 渡辺裕子, 大須賀穣, 藤井知行, 矢野哲, 上妻志郎
  • Journal Title: 日本受精着床学会誌 Volume: 30 Pages: 65-9
  • Peer Reviewed
• [Journal Article] Predictive factors for recurrence of ovarian mature cystic teratomas after surgical excision. (2013)
  • Author(s): Harada M, Osuga Y, Fujimoto A, Fujimoto A, Fujii T, Yano T, Kozuma S
  • Journal Title: Eur J Obstet Gyncol Reprod Biol. Volume: 171 Pages: 325-8
  • Peer Reviewed
• [Journal Article] 採卵数の少ない症例にICSIは必要か (2013)
  • Author(s): 大井なぎさ 原田美由紀 藤本晃久 大須賀穣
  • Journal Title: 産婦人科の実際 Volume: 62 Pages: 1279-84
  • NAID: 40019806404
• [Journal Article] The Localization and Regulation of Proprotein Convertase Subtilisin/Kexin (PCSK) 6 in Human Ovary. (2012)
  • Author(s): Akiyama I, Yoshino O, Osuga Y, Shi J, Hirota Y, Hirata T, Harada M, Koga K, Fujimoto A, Yano T, Taketani Y.
  • Journal Title: Am J Reprod Immunol. Volume: 68 Issue: 6 Pages: 491-498
  • DOI: 10.1111/aji.12003
  • Peer Reviewed
• [Journal Article] Interleukin-17A is present in neutrophils in endometrioma and stimulates the secretion of growth-regulated oncogene-α (Gro-α) from endometrioma stromal cells (2012)
  • Author(s): Takamura M, Osuga Y, Izumi G, Yoshino O, Koga K, Saito A, Hirata T, Hirota Y, Harada M, Hasegawa A, Taketani Y
  • Journal Title: Fertil Steril Volume: 98 Issue: 5 Pages: 1218-24
  • DOI: 10.1016/j.fertnstert.2012.07.1117
  • Peer Reviewed
• [Journal Article] Urata Y, Osuga Y, Izumi G, Takamura M, Koga K, Nagai M, Harada M, Hirata T, Hirota Y, Yoshino O, Taketani Y (2012)
  • Author(s): Interleukin-1β stimulates the secretion of thymic stromal lymphopoietin (TSLP) from endometrioma stromal cells: possible involvement of TSLP in endometriosis.
  • Journal Title: Hum Reprod Volume: 27 Issue: 10 Pages: 3028-35
  • DOI: 10.1093/humrep/des291
  • Peer Reviewed
• [Journal Article] Growth differentiation factor 3 is induced by bone morphogenetic protein 6 (BMP-6) and BMP-7 and increases luteinizing hormone receptor messenger RNA expression in human granulosa cells (2012)
  • Author(s): Shi J, Yoshino O, Osuga Y, Akiyama I, Harada M, Koga K, Fujimoto A, Yano T, Taketani Y.
  • Journal Title: Fertil Steril. Volume: 97 Issue: 4 Pages: 979-983
  • DOI: 10.1016/j.fertnstert.2012.01.100
  • Peer Reviewed
• [Journal Article] Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss (2012)
  • Author(s): Tsutsumi R, Fujimoto A, Osuga Y, Harada M, Takemura Y, Koizumi M, Yano T, Taketani Y.
  • Journal Title: Gynecol Endocrinol Volume: 28 Issue: 6 Pages: 460-462
  • DOI: 10.3109/09513590.2011.633650
  • Peer Reviewed
• [Journal Article] The localization and regulation of proprotein convertase subtilisin/kexin (PCSK) 6 in human ovary. (2012)
  • Author(s): Akiyama I, Yoshino O, Osuga Y, Shi J, Hirota Y, Hirata T, Harada M, Koga K, Fujimoto A, Yano T, Taketani Y
  • Journal Title: Am J Reprod Immunol. Volume: 68 Pages: 491-8
  • Peer Reviewed
• [Journal Article] Interleukin-17A is present in neutrophils in endometrioma and stimulates the secretion of growth-regulated oncogene-α (Gro-α) from endometrioma stromal cells. (2012)
  • Author(s): Takamura M, Osuga Y, Izumi G, Yoshino O, Koga K, Saito A, Hirata T, Hirota Y, Harada M, Hasegawa A, Taketani Y.
  • Journal Title: Fertil Steril Volume: 98
  • Peer Reviewed
• [Journal Article] Interleukin-1β stimulates the secretion of thymic stromal lymphopoietin (TSLP) from endometrioma stromal cells: possible involvement of TSLP in endometriosis. (2012)
  • Author(s): Urata Y, Osuga Y, Izumi G, Takamura M, Koga K, Nagai M, Harada M, Hirata T, Hirota Y, Yoshino O, Taketani Y.
  • Journal Title: Hum Reprod. Volume: 27 Pages: 3028-35
  • Peer Reviewed
• [Journal Article] Growth differentiation factor 3 is induced by bone morphogenetic protein 6 (BMP-6) and BMP-7 and increases luteinizing hormone receptor messenger RNA expression in human granulosa cells. (2012)
  • Author(s): Shi J, Yoshino O, Osuga Y, Akiyama I, Harada M, Koga K, Fujimoto A, Yano T, Taketani Y.
  • Journal Title: Fertil Steril Volume: 97 Pages: 979-83
  • Peer Reviewed
• [Journal Article] Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss. (2012)
  • Author(s): Tsutsumi R, Fujimoto A, Osuga Y, Harada M, Takemura Y, Koizumi M, Yano T, Taketani Y.
  • Journal Title: Gynecol Endocrinol Volume: 28 Pages: 460-2
  • Peer Reviewed
• [Presentation] Evidence of the activation of unfolded protein response in cumulus cells during follicular growth and its possible role in oocyte maturation (2013)
  • Author(s): Harada M, Osuga Y, Yoshino O, Fujii T, Yano T, Kozuma S
  • Organizer: 95th The Endocrine Society's Annual Meeting
  • Place of Presentation: サンフランシスコ(米国)
• [Presentation] 卵巣成熟嚢胞性奇形腫の嚢腫摘出後の再発に関する検討 (2013)
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  • Organizer: 第65回日本産科婦人科学会
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• [Presentation] 低用量ピルとジエノゲストの子宮内膜症性卵巣嚢胞摘出術後再発予防効果の比較検討 (2013)
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  • Organizer: 第65回日本産科婦人科学会
  • Place of Presentation: 札幌
• [Presentation] (2013)
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  • Organizer: 第53回日本産科婦人科内視鏡学会
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• [Presentation] (2013)
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  • Organizer: 第58回日本生殖医学会
  • Place of Presentation: 神戸
• [Presentation] Evidence of the activation of unfolded protein response in cumulus cells during follicular growth and its possible role in oocyte maturation (2013)
  • Author(s): M Harada, Y Osuga, O Yoshino, T Fujii, T Yano, S Kozuma
  • Organizer: 95th The Endocrine Society's Annual Meeting
  • Place of Presentation: San Franｓisco, CA, USA
• [Presentation] 卵巣成熟嚢胞性奇形腫の嚢腫摘出術後の再発に関する検討 (2013)
  • Author(s): 藤本麻葉、原田美由紀、大須賀穣、藤本晃久、平池修、藤井知行、矢野哲、上妻志郎
  • Organizer: 第65回日本産科婦人科学会
  • Place of Presentation: 札幌
• [Presentation] 腹腔鏡下子宮内膜症性卵巣嚢胞摘出術の、卵巣機能に与える影響の検討 (2013)
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  • Organizer: 第53回日本産科婦人科内視鏡学会
  • Place of Presentation: 名古屋
• [Presentation] 凍結融解胚移植例と新鮮胚移植例の妊娠初期の血清hCG値推移の比較検討 (2013)
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  • Organizer: 第58回日本生殖医学会
  • Place of Presentation: 神戸
• [Presentation] 40歳以上の不妊患者におけるARTの予後規定因子の検討 (2012)
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  • Organizer: 第57回日本生殖医学会
  • Place of Presentation: 長崎
• [Presentation] 採卵数の少ない症例に ICSI は必要か (2012)
  • Author(s): 大井なぎさ, 原田美由紀, 藤本晃久, 大須賀穣, 大石元, 平田哲也, 堤亮, 森嶋かほる, 渡辺裕子, 増澤菜美, 藤井知行, 矢野哲, 上妻志郎
  • Organizer: 第57回日本生殖医学会
  • Place of Presentation: 長崎
• [Presentation] 採卵数の少ない症例にICSIは必要か (2012)
  • Author(s): 大井なぎさ、原田美由紀、藤本晃久、大須賀穣、大石元、平田哲也、堤亮、森嶋かほる、渡辺裕子、増澤菜美、藤井知行、矢野哲、上妻志郎
  • Organizer: 第57回日本生殖医学会
  • Place of Presentation: 長崎