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Super流産の原因遺伝子の同定と胎児染色体正常原因不明習慣流産の病態解明

Research Project

Project/Area Number 23K24486
Project/Area Number (Other) 22H03227 (2022-2023)
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund (2024)
Single-year Grants (2022-2023)
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionNagoya City University

Principal Investigator

杉浦 真弓  名古屋市立大学, 医薬学総合研究院(医学), 教授 (30264740)

Co-Investigator(Kenkyū-buntansha) 奥野 友介  名古屋市立大学, 医薬学総合研究院(医学), 教授 (00725533)
松浦 栄次  岡山大学, 中性子医療研究センター, 教授 (20181688)
大石 久史  名古屋市立大学, 医薬学総合研究院(医学), 教授 (30375513)
Project Period (FY) 2022-04-01 – 2026-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
Fiscal Year 2025: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2024: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2023: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2022: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords不育症 / 習慣流産 / 全ゲノムトリオ解析 / メタボロミクス解析
Outline of Research at the Start

不育症の原因精査により、胎児染色体正常の真の原因不明は25%に留まる。10回以上の難治性習慣流産“Super流産”は挑戦的治療にも抵抗し出産不可能である。本研究ではSuper流産患者とその両親の全ゲノムトリオ解析とマウスゲノム編集による実証という全く新しい手法により、原因遺伝子を同定する。また、メタボロミクス解析を行い、特異的代謝産物を調べることからも原因解明を目指す。これらの成果により個々の患者の原因から個別化医療を確立する新たな治療戦略に発展できる可能性を持つ。同定された遺伝子や特異的代謝物は妊娠維持に必須の遺伝子、因子であるため、ヒト妊娠維持メカニズムの根源に迫る重要な基盤研究になる。

Outline of Annual Research Achievements

5家系の全ゲノムタイピング、全ゲノム解析を行った。
参照ヒトゲノム配列と比較し変異を同定する(Alignment)。得られたリード(塩基配列)は、Burrows-Wheeler Alignment ToolやNovoalignなどのソフトを用いてインフォマティクス解析後にヒトの参照塩基配列に貼り付ける。Genome Analysis Tool KitやSnpEffなどを用いて両親と異なる変異を調べる(Variant Call)。一塩基置換Single nucleotide variant (SNV)、短い挿入・欠失insertion/deletion (Indel)がコールされる。
病的候補遺伝子の絞り込み。健常人のバリアント情報ExAC, ESP6500, ToMMo、ヒトの変異情報が網羅されているHuman Gene Mutation Database、バリアントの病的意義をアミノ酸の保存性や変化を元に予測する。in silico解析ツールでの予測スコアSIFT, PolyPhen-2, Mutation Taster, CADDを用いる。
変異候補の絞り込み(Filtering)は新規ヘテロに着目する。父由来ヘテロは除外しない。American College of Medical Genetics (ACMG) / American Molecular Pathology (AMP) をもとに“Pathogenic” “Benign” “Uncertain Significance ”を参照する。有望な変異がないため遺伝子改変マウスの作成に至っていない。
健常人血液を用いてメタボロミクス解析法を確立した。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

10回以上流産の症例は希少であるため。
先行研究を参考にしてEDTA血、クエン酸加血など採血条件と実験方法を確立するのに時間がかかった。

Strategy for Future Research Activity

検体収集に努める。
7-1月に申蓮花研究協力者が中国から岡山大学に来日するため、集中的に測定する。採血条件が決定したのでそれまでに検体収集を行う。胎児染色体正常が確認された習慣流産患者20人の血漿(非妊時)と流産時子宮脱落膜およびコントロールとして流産歴のない20人の人工妊娠中絶時の脱落膜と健常女性20人の血漿(非妊時)を収集する。
ノンターゲットLC-MS/MS。1000種類を超える代謝産物のノンターゲットLC-MS/MS解析を行い、原因不明習慣流産群、健常女性群の代謝プロファイルの差を調べる。島津製作所 LC/MS/MS Method packageを用いてクラスター分析する。

Report

(1 results)
  • 2022 Annual Research Report
  • Research Products

    (14 results)

All 2023 2022

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 9 results) Presentation (2 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results)

  • [Journal Article] The uncertain science of preimplantation genetic testing in Japan2022

    • Author(s)
      Mayumi Sugiura-Ogasawara, Takeshi Sato
    • Journal Title

      Nature Mecicine

      Volume: 28 Issue: 9 Pages: 1732-1733

    • DOI

      10.1038/s41591-022-01920-1

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Characteristic DNA methylation profiles of chorionic villi in recurrent miscarriage2022

    • Author(s)
      Matsumoto Y, Shinjo K, Mase S, Fukuyo M, Aoki K, Ozawa F, Yoshihara H, Goto S, Kitaori T, Ozaki Y, Takahashi S, Kaneda A, Sugiura-Ogasawara M, Kondo Y.
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 11673-11673

    • DOI

      10.1038/s41598-022-15656-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of Ready-Meal Consumption during Pregnancy on Birth Outcomes: The Japan Environment and Children’s Study2022

    • Author(s)
      Tamada Hazuki、Ebara Takeshi、Matsuki Taro、Kato Sayaka、Sato Hirotaka、Ito Yuki、Saitoh Shinji、Kamijima Michihiro、Sugiura-Ogasawara Mayumi、on behalf of the Japan Environment and Children’s Study Group
    • Journal Title

      Nutrients

      Volume: 14 Issue: 4 Pages: 895-895

    • DOI

      10.3390/nu14040895

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Depression symptoms during pregnancy and postpartum in patients with recurrent pregnancy loss and infertility: The Japan environment and children’s study2022

    • Author(s)
      Otani-Matsuura Ayano、Sugiura-Ogasawara Mayumi、Ebara Takeshi、Matsuki Taro、Tamada Hazuki、Yamada Yasuyuki、Omori Toyonori、Kato Sayaka、Kano Hirohisa、Kaneko Kayo、Matsuzaki Kazuki、Saitoh Shinji、Kamijima Michihiro
    • Journal Title

      Journal of Reproductive Immunology

      Volume: 152 Pages: 103659-103659

    • DOI

      10.1016/j.jri.2022.103659

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Abnormal ciliogenesis in decidual stromal cells in recurrent miscarriage2022

    • Author(s)
      Hassan Esraa、Kojima Ryuji、Ozawa Fumiko、Yoshihara Hiroyuki、Goto Shinobu、Kitaori Tamao、Inagaki Hiroshi、Kato Yoichi、Sugiura-Ogasawara Mayumi
    • Journal Title

      Journal of Reproductive Immunology

      Volume: 150 Pages: 103486-103486

    • DOI

      10.1016/j.jri.2022.103486

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Repeated maternal non-responsiveness to baby's crying during postpartum and infant neuropsychological development: The Japan Environment and Children’s Study2022

    • Author(s)
      Matsuki Taro、Ebara Takeshi、Tamada Hazuki、Kato Sayaka、Kaneko Kayo、Kano Hirohisa、Matsuzaki Kazuki、Sato Hirotaka、Minato Kyoko、Sugiura-Ogasawara Mayumi、Saitoh Shinji、Kamijima Michihiro
    • Journal Title

      Child Abuse & Neglect

      Volume: 127 Pages: 105581-105581

    • DOI

      10.1016/j.chiabu.2022.105581

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Does a cervical pessary reduce the rate of preterm birth in women with a short cervix?2022

    • Author(s)
      Kumagai Kyoko、Murotsuki Jun、Dohi Satoshi、Nishikawa Naomi、Kimura Naomi、Nomiyama Makoto、Osaga Satoshi、Hashimoto Hiroya、Nakai Akihito、Sugiura-Ogasawara Mayumi、Ozaki Yasuhiko
    • Journal Title

      Journal of Perinatal Medicine

      Volume: 50 Issue: 8 Pages: 1107-1114

    • DOI

      10.1515/jpm-2021-0688

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Simultaneous quantification of pyrethroid metabolites in urine of non-toilet-trained children in Japan2022

    • Author(s)
      Ueyama Jun、Ito Yuki、Hamada Risa、Oya Naoko、Kato Sayaka、Matsuki Taro、Tamada Hazuki、Kaneko Kayo、Saitoh Shinji、Sugiura-Ogasawara Mayumi、Ebara Takeshi、Kamijima Michihiro
    • Journal Title

      Environmental Health and Preventive Medicine

      Volume: 27 Issue: 0 Pages: 25-25

    • DOI

      10.1265/ehpm.21-00037

    • ISSN
      1342-078X, 1347-4715
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Abnormal accumulation of OFD1 in endometrial cancer with poor prognosis inhibits ciliogenesis2022

    • Author(s)
      Kojima Ryuji, Hassan Esraa, Ozawa Fumiko,Yamada,Namikawa Chisato, Ogawa Shino, Mase Shoko, Goto Shinobu, Nishikawa Ryutaro, Inagaki Hiroshi, Kato Yoichi, Sugiura-Ogasawara Mayumi
    • Journal Title

      Oncology Letters

      Volume: 24 Issue: 1 Pages: 214-214

    • DOI

      10.3892/ol.2022.13334

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High Maternal Total Cholesterol Is Associated With No-Catch-up Growth in Full-Term SGA Infants: The Japan Environment and Children's Study2022

    • Author(s)
      Kaneko K, Ito Y, Ebara T, Kato S, Matsuki T, Tamada H, Sato H, Saitoh S, Sugiura-Ogasawara M, Yatsuya H, Kamijima M.
    • Journal Title

      Front Endocrinol (Lausanne)

      Volume: 14;13 Pages: 939366-939366

    • DOI

      10.3389/fendo.2022.939366

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epidemiological Studies of Children’s Gut Microbiota: Validation of Sample Collection and Storage Methods and Microbiota Analysis of Toddlers’ Feces Collected from Diapers2022

    • Author(s)
      Tamada Hazuki、Ito Yuki、Ebara Takeshi、Kato Sayaka、Kaneko Kayo、Matsuki Taro、Sugiura-Ogasawara Mayumi、Saitoh Shinji、Kamijima Michihiro
    • Journal Title

      Nutrients

      Volume: 14 Issue: 16 Pages: 3315-3315

    • DOI

      10.3390/nu14163315

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantitative Measurement of Phthalate Exposure Biomarker Levels in Diaper-Extracted Urine of Japanese Toddlers and Cumulative Risk Assessment: An Adjunct Study of JECS Birth Cohort2022

    • Author(s)
      Mohanto Nayan C.、Ito Yuki、Kato Sayaka、Ebara Takeshi、Kaneko Kayo、Tsuchiyama Tomoyuki、Sugiura-Ogasawara Mayumi、Saitoh Shinji、Kamijima Michihiro
    • Journal Title

      Environmental Science & Technology

      Volume: 57 Issue: 1 Pages: 395-404

    • DOI

      10.1021/acs.est.2c04816

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Pregnancy outcomes among women with RPL.2023

    • Author(s)
      Sugiura-Ogasawara M
    • Organizer
      6th World Congress on Recurrent Pregnancy Loss
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Assessment of recurrent pregnancy loss and fetal death. aPL and other factors.2022

    • Author(s)
      Sugiura-Ogasawara M
    • Organizer
      17th International Congress on Antiphospholipid Antibodies.
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2022-04-19   Modified: 2024-12-25  

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