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Elucidation of pathogenesis and establishment of early diagnosis of autoimmune-related reproductive dysfunction by focusing on novel autoantibody-target antigens

Research Project

Project/Area Number 20H03819
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionGunma University

Principal Investigator

Akira Iwase  群馬大学, 大学院医学系研究科, 教授 (20362246)

Co-Investigator(Kenkyū-buntansha) 北原 慈和  群馬大学, 医学部附属病院, 講師 (20714728)
大須賀 智子  名古屋大学, 医学部附属病院, 講師 (30778296)
小松 紘司  愛知医科大学, 医学部, 講師 (40456893)
小谷 友美  名古屋大学, 医学部附属病院, 病院教授 (70359751)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2023: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2022: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Keywords卵巣機能不全 / 自己免疫 / 自己抗体 / POTE / FOXL2 / PCOS / 生殖医学 / 反復流産
Outline of Research at the Start

不妊症・不育症には自己免疫疾患が合併することがあるが、その詳細は不明である。我々は患者血清中に存在する自己抗体とその標的タンパクProstate, ovary, testis, ankyrin domain family member F (POTEF)を同定した。POTEFは卵巣、胎盤に特異性高く発現し、自己免疫機序によるPOTEFの障害が卵巣機能不全、反復流産の病態であるという仮説をたてた。
卵巣、胎盤におけるPOTEFの機能解析を行うとともに、抗POTE抗体をマウスに投与し、自己免疫機序による病態の再現が可能かどうか検証する。抗POTEF抗体のアッセイ系を用い臨床的検討もあわせて行う。

Outline of Final Research Achievements

We found autoantibodies that react with ovarian granulosa cells in the serum of thyroid autoantibody-positive ovarian insufficiency patients and identified their target protein, POTEF.
We demonstrated that POTEF is expressed in human ovarian granulosa cells and oocytes, and that its expression is altered by follicle development and suppresses cell proliferation. We established the basis for an anti-POTEF antibody assay system in human serum using purified POTEF protein and found that anti-POTEF antibody titers in sera from patients with ovarian insufficiency were significantly higher than those from women with normal ovarian function.
We found a binding site for FOXL2, a transcription factor important for ovarian differentiation, in the promoter region of POTEF, and found a trend toward higher FOXL2 levels in women with PCOS, whose main symptom is ovulatory failure.

Academic Significance and Societal Importance of the Research Achievements

現在日本では少子化が問題となっているが、これには晩産化をともなっている。一方で40歳未満で卵巣機能が停止する早発閉経の頻度は増加し、約100人に1人を超えると言われている。近年、卵巣機能維持の指標である卵巣予備能検査が注目され普及しつつある。しかしながら、早発閉経の病態に即した卵巣機能の予測方法は存在せず、挙児希望時点で治療困難な卵巣機能不全を呈する女性が一定数存在する。本研究成果は、卵巣機能不全に対するリスク因子の検査手法の開発であり、卵巣予備能検査と組み合わせることで女性のライフプランニングに役立つ可能性があるだけでなく、卵巣機能不全に対する新規治療標的を提案するものである。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (7 results)

All 2023 2022 2021

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (4 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Tamoxifen Activates Dormant Primordial Follicles in Mouse Ovaries2022

    • Author(s)
      Wei Wei、Komatsu Kouji、Osuka Satoko、Murase Tomohiko、Bayasula Bayasula、Nakanishi Natsuki、Nakamura Tomoko、Goto Maki、Iwase Akira、Masubuchi Satoru、Kajiyama Hiroaki
    • Journal Title

      Reproductive Sciences

      Volume: Online ahead of print. Issue: 12 Pages: 3404-3412

    • DOI

      10.1007/s43032-022-00896-0

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Primate-specific POTE-actin gene could play a role in human folliculogenesis by controlling the proliferation of granulosa cells2021

    • Author(s)
      Kasahara Y, Osuka S, Takasaki N, Bayasula, Koya Y, Nakanishi N, Murase T, Nakamura T, Goto M, Iwase A, Kajiyama H
    • Journal Title

      Cell Death Discov

      Volume: 7 Issue: 1 Pages: 186-186

    • DOI

      10.1038/s41420-021-00566-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of hypothyroidism and thyroid autoimmunity on the ovarian reserve: A systematic review and meta-analysis2021

    • Author(s)
      Hasegawa Y, Kitahara Y, Osuka S, Tsukui Y, Kobayashi M, Iwase A.
    • Journal Title

      Reprod Med Biol

      Volume: 21 Issue: 1

    • DOI

      10.1002/rmb2.12427

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 転写因子FOXL2による多嚢胞性卵巣症候群の病態検討2023

    • Author(s)
      長谷川祐子、岩瀬 明
    • Organizer
      第96回日本内分泌学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] FOXL2 expression in the ovary of women with PCOS2023

    • Author(s)
      Hasegawa Y, Nakamura O, Inoue N, Iwase A
    • Organizer
      IFFS World Congress 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PCOSの病態・診断・治療-動物モデルから黄体補充まで2023

    • Author(s)
      岩瀬 明
    • Organizer
      第28回日本生殖内分泌学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 多嚢胞性卵巣症候群におけるFOXL2解析2022

    • Author(s)
      長谷川祐子、北原慈和、津久井優美子、小林未央、岩瀬明
    • Organizer
      日本生殖内分泌学会
    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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