Elucidation of the PGC-1 alpha-mediated pathway of endometriosis and establishment of molecular targeted therapy

• Project/Area Number: 19K24048
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Kataoka Hisashi 京都府立医科大学, 医学(系)研究科(研究院), 助教 (90849027)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PGC-1α / 低栄養 / 代謝 / 低酸素 / 子宮内膜症

Outline of Research at the Start

子宮内膜症の発症・進展機序はいまだ不明な点が多い。我々はこれまでに転写共役因子であるPGC-1αが子宮内膜症における細胞の増殖やエストロゲンの異常産生、局所の炎症惹起、抗アポトーシスの獲得など様々な病態形成に重要な役割を果たすことを明らかにしてきた。さらに病巣局所で異常産生されているTNF-αがさらにPGC-1αを誘導することを明らかにし、内分泌-炎症のクロストークの存在について示した。
本研究ではPGC-1αが相互作用を示すとされる核内受容体の同定とその複合体が及ぼすシグナル伝達経路を明らかにすることで、内分泌・炎症の両側面から病巣進展を制御しうる新たな治療戦略の分子基盤を確立させる。

Outline of Final Research Achievements

We have focused on the role of PGC-1α in the pathophysiology and progression of endometriosis. It was shown that RXR receptors, which are coactivators with PPAR receptors and other receptors, may act as homodimers and monomers in endometriosis. We also showed that PGC-1α may play a role in the pathophysiology of endometriosis by enhancing its function in local hypoxia and undernutrition, affecting glucogenesis and energy metabolism. In mice, we found that HX531, which suppresses RXR function, reduced the number and weight of endometriotic tissues. These results suggest that PGC-1α plays a central role in the pathophisiology of endometriosis and that HX531 may be useful as a novel therapeutic agent.

Academic Significance and Societal Importance of the Research Achievements

子宮内膜症は生殖年齢女性の約6-10％が罹患し、骨盤痛や不妊の原因となり生活のQOLを著しく低下させる。その病因は不明な点が多く、また従来の治療では再発のリスクや妊娠希望女性には使いづらいなど、新しい治療法の開発が望まれている。われわれが見出したPGC-1αは子宮内膜症の病態形成に中心的な役割を果たす因子であり、その詳細な検討から子宮内膜症の発症機序や増悪のメカニズムの解明に期待できる。またPGC-1αが共役するRXRの阻害剤を用いることで子宮内膜症の治療につながる可能性を見出した。これらは今までとは違う側面からの新規治療法であり、子宮内膜症の克服への一助となると考えられる。

Research Products

• [Journal Article] Interleukin‐9 produced by helper T cells stimulates interleukin‐8 expression in endometriosis (2020)
  • Author(s): Tarumi Yosuke、Mori Taisuke、Okimura Hiroyuki、Maeda Eiko、Tanaka Yukiko、Kataoka Hisashi、Ito Fumitake、Koshiba Akemi、Kusuki Izumi、Kitawaki Jo
  • Journal Title: American Journal of Reproductive Immunology Volume: -
  • DOI: 10.1111/aji.13380
  • Peer Reviewed
• [Journal Article] Atherosclerosis-related biomarkers in women with endometriosis: The effects of dienogest and oral contraceptive therapy (2020)
  • Author(s): Maeda Eiko、Koshiba Akemi、Mori Taisuke、Ito Fumitake、Kataoka Hisashi、Okimura Hiroyuki、Sugahara Takuya、Tarumi Yosuke、Kusuki Izumi、Khan Khaleque N.、Kitawaki Jo
  • Journal Title: European Journal of Obstetrics & Gynecology and Reproductive Biology: X Volume: 7 Pages: 100108-100108
  • DOI: 10.1016/j.eurox.2020.100108
  • Peer Reviewed / Open Access
• [Journal Article] Peroxisome proliferator-activated receptor-γ coactivator 1α-mediated pathway as a possible therapeutic target in endometriosis. (2019)
  • Author(s): Kataoka H, Mori T, Okimura H, Matsushima H, Ito F, Koshiba A, Tanaka Y, Akiyama K, Maeda E, Sugahara T, Tarumi Y, Kusuki I, Khan KN, Kitawaki J.
  • Journal Title: Human Reproduction Volume: 34 Pages: 1019-1029
  • DOI: 10.1093/humrep/dez067
  • Peer Reviewed
• [Journal Article] Local estrogen formation and its regulation in endometriosis (2019)
  • Author(s): Mori Taisuke、Ito Fumitake、Koshiba Akemi、Kataoka Hisashi、Takaoka Osamu、Okimura Hiroyuki、Khan Khaleque N.、Kitawaki Jo
  • Journal Title: Reproductive Medicine and Biology Volume: 18 Pages: 305-311
  • DOI: 10.1002/rmb2.12285
  • Peer Reviewed / Open Access
• [Journal Article] PGC-1αは子宮内膜症病態形成に関与する (2019)
  • Author(s): 片岡 恒
  • Journal Title: 日本生殖内分泌学会雑誌 Volume: 24 Pages: 9-11
• [Journal Article] Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells. (2019)
  • Author(s): Kokabu T, Mori T, Matsushima H, Yoriki K, Kataoka H, Tarumi Y, Kitawaki J.
  • Journal Title: Cell Oncol (Dordr) Volume: 42(2) Pages: 223-235
  • DOI: 10.1007/s13402-019-00423-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Equilin in conjugated equine estrogen increases monocyte-endothelial adhesion via NF-κB signaling (2019)
  • Author(s): Ito F, Mori T, Tarumi Y, Okimura H, Kataoka H, Tanaka Y, Koshiba A, Kitawaki J
  • Journal Title: PLOS ONE Volume: 14 Pages: 0211462-0211462
  • DOI: 10.1371/journal.pone.0211462
  • Peer Reviewed / Open Access
• [Presentation] 腸型腺癌への悪性転化をきたした卵巣成熟奇形腫の1例 (2020)
  • Author(s): 片岡 恒、垂水 洋輔、古株 哲也、寄木 香織、森 泰輔、北脇 城
  • Organizer: 第62回日本婦人科腫瘍学会学術講演会
• [Presentation] Hepcidin as a key regulator of iron in the pathogenesis of endometriosis and a new biomarker (2019)
  • Author(s): Hisashi Kataoka, Taisuke Mori, Fumitake, Ito, Akemi, Koshiba, Hiroyuki Okimura, Eiko Maeda, Yosuke Tarumi, Takuya Sugahara, Koki Shimura, Izumi Kusuki, and Jo Kitawaki
  • Organizer: The 71th Annual Congress of the Japan Society of Obstetrics and Gynecology
• [Presentation] Hepcidin promotes iron accumulation and triggers inflammatory features of normal endometrium (2019)
  • Author(s): Hisashi Kataoka, Taisuke Mori, Izumi Kusuki Khaleque N Khan , Jo Kitawaki
  • Organizer: Asian Conference of Endometriosis
  • Int'l Joint Research
• [Book] 子宮内膜症・子宮腺筋症ー診断アトラス＆新たな治療戦略 (2021)
  • Author(s): 大須賀穣、甲賀かをり
  • Total Pages: 304
  • Publisher: 中山書店
  • ISBN: 9784521749105
• [Book] 産科と婦人科 (2020)
  • Author(s): 片岡 恒
  • Total Pages: 130
  • Publisher: (株)診断と治療社