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Optogenetic regulation of function, regeneration and diseases of the female reproductive organ using stem cell and genome editing technologies

Research Project

Project/Area Number 20H03826
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 InstitutionKeio University

Principal Investigator

MARUYAMA Tetsuo  慶應義塾大学, 医学部(信濃町), 准教授 (10209702)

Co-Investigator(Kenkyū-buntansha) 佐藤 守俊  東京大学, 大学院総合文化研究科, 教授 (00323501)
高尾 知佳  慶應義塾大学, 医学部(信濃町), 共同研究員 (40612429)
升田 博隆  慶應義塾大学, 医学部(信濃町), 講師(非常勤) (80317198)
内田 浩  慶應義塾大学, 医学部(信濃町), 講師 (90286534)
宮崎 薫  慶應義塾大学, 医学部, 研究員 (90445370)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywords光遺伝学 / ゲノム編集 / 幹細胞 / 再生医学 / 子宮 / 子宮内膜症 / 子宮筋腫 / 子宮内膜癌 / 子宮再生 / 脱細胞化 / 子宮内膜 / 光制御
Outline of Research at the Start

本研究では,①光照射によるゲノム編集により雌性生殖器官の特定の細胞における特定の遺伝子の発現を時空間的に制御するシステム,②雌性生殖器官から細胞を除去して得られた細胞外基質のみを有する足場(脱細胞化雌性生殖器官骨格)を細胞・組織の導入・運搬・維持の担体として用いるシステム,③幹細胞を起点として雌性生殖器官の構成細胞・組織を作製するシステム(幹細胞工学),の三つのシステムを単独あるいは複合的に開発し用いることを通じて,雌性生殖器官の機能・再生・疾患を制御する新しい研究ツールと治療技術に関する基盤知見を得ることと,それらを用いて疾患の病態メカニズムを解明する.

Outline of Final Research Achievements

In this study we aimed to optogenetically regulate the function, regeneration, diseases of the female reproductive organ with the combinatory use of stem cell biology, genome editing technology, and tissue engineering. As a result, we were able to control embryo implantation, one of the important uterine functions, in a spatiotemporal manner through optogenetic genome editing of a molecule essential for implantation in mice. To achieve an efficient introduction of the optogenetic system into the tissue and organ, we developed a novel bioengineering method for the partial regeneration of the uterus in rats. To obtain the basis for the optogenetic regulation of the genesis and progression of uterus-associated disorders, we explored the roles of stem cells and genomic abnormalities in the pathogenesis of endometriosis, endometrial cancer, and leiomyoma.

Academic Significance and Societal Importance of the Research Achievements

本研究において示された光照射による着床制御は,不妊症,不育症,および子宮に関連する周産期疾患や腫瘍性疾患に対する光照射治療という新しい治療様式・戦略を提示することに加えて,その実現化に向けての基盤となる成果である.さらに,時空間的な現象である着床を光照射のオンオフで自在に解析できる新しい研究手法であることと,その結果もたらされ得る着床のメカニズムのさらなる解明が期待できる点で学術的意義が高い.新しい子宮の再生・再建技術ならびに子宮関連疾患における幹細胞とゲノム異常の役割の解明は,光照射治療の実現化に向けての科学的根拠と技術基盤を与えうる点でも学術的社会的意義が高い成果である.

Report

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

    (25 results)

All 2023 2022 2021 2020

All Journal Article (15 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 13 results,  Open Access: 14 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results)

  • [Journal Article] A Decellularized Uterine Endometrial Scaffold Enhances Regeneration of the Endometrium in Rats2023

    • Author(s)
      Yoshimasa Yushi、Takao Tomoka、Katakura Satomi、Tomisato Shoko、Masuda Hirotaka、Tanaka Mamoru、Maruyama Tetsuo
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 8 Pages: 7605-7605

    • DOI

      10.3390/ijms24087605

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inflammatory Cytokine-Induced HIF-1 Activation Promotes Epithelial?Mesenchymal Transition in Endometrial Epithelial Cells2023

    • Author(s)
      Hashimoto Yoshiko、Tsuzuki-Nakao Tomoko、Kida Naoko、Matsuo Yoshiyuki、Maruyama Tetsuo、Okada Hidetaka、Hirota Kiichi
    • Journal Title

      Biomedicines

      Volume: 11 Issue: 1 Pages: 210-210

    • DOI

      10.3390/biomedicines11010210

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Guidelines for Reproductive Medicine in Japan2022

    • Author(s)
      Yamada Mitsutoshi、Osuka Satoko、Kanasaki Haruhiko、Kawano Yasushi、Kawamura Kazuhiro、Kishi Hiroshi、Kimura Fuminori、Kuroda Shinnosuke、Kuwahara Akira、Tamura Hiroshi、Jwa Seung Chik、Baba Tsuyoshi、Harada Miyuki、Hirata Tetsuya、Yoshino Osamu、Hirota Yasushi、Tsujimura Akira、Kuji Naoaki、Osuga Yutaka
    • Journal Title

      Reproductive Medicine and Biology

      Volume: 21 Issue: 1 Pages: 1-1

    • DOI

      10.1002/rmb2.12483

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sorafenib targets and inhibits the oncogenic properties of endometrial cancer stem cells via the RAF/ERK pathway2022

    • Author(s)
      Takao Tomoka、Masuda Hirotaka、Kajitani Takashi、Miki Fumie、Miyazaki Kaoru、Yoshimasa Yushi、Katakura Satomi、Tomisato Shoko、Uchida Sayaka、Uchida Hiroshi、Tanaka Mamoru、Maruyama Tetsuo
    • Journal Title

      Stem Cell Research & Therapy

      Volume: 13 Issue: 1 Pages: 225-225

    • DOI

      10.1186/s13287-022-02888-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A mediator complex subunit 12 gain-of-function mutation induces partial leiomyoma cell properties in human uterine smooth muscle cells2022

    • Author(s)
      Takao Tomoka、Ono Masanori、Yoshimasa Yushi、Masuda Hirotaka、Maruyama Tetsuo
    • Journal Title

      F&S Science

      Volume: 3 Issue: 3 Pages: 288-298

    • DOI

      10.1016/j.xfss.2022.04.002

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two ovarian candidate enhancers, identified by time series enhancer RNA analyses, harbor rare genetic variations identified in ovarian insufficiency2022

    • Author(s)
      Nakagawa Ryuichi et al.
    • Journal Title

      Human Molecular Genetics

      Volume: - Issue: 13 Pages: 2223-2235

    • DOI

      10.1093/hmg/ddac023

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers2022

    • Author(s)
      Fujita Arimi、Noguchi Saki、Hamada Rika、Inoue Satoko、Shimada Tsutomu、Katakura Satomi、Maruyama Tetsuo、Sai Yoshimichi、Nishimura Tomohiro、Tomi Masatoshi
    • Journal Title

      Pharmaceutical Research

      Volume: - Issue: 7 Pages: 1645-1658

    • DOI

      10.1007/s11095-022-03165-6

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A revised stem cell theory for the pathogenesis of endometriosis2022

    • Author(s)
      Maruyama T
    • Journal Title

      J Pers Med

      Volume: 12 Issue: 2 Pages: 216-216

    • DOI

      10.3390/jpm12020216

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bioengineering of the Uterus2021

    • Author(s)
      Yoshimasa Y, Maruyama T
    • Journal Title

      Reprod Sci

      Volume: 28 Issue: 6 Pages: 1596-1611

    • DOI

      10.1007/s43032-021-00503-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Optical Control of Genome Editing by Photoactivatable Cas92021

    • Author(s)
      Otabe T, Nihongaki Y, Sato M
    • Journal Title

      Methods Mol Biol

      Volume: 2312 Pages: 225-233

    • DOI

      10.1007/978-1-0716-1441-9_13

    • ISBN
      9781071614402, 9781071614419
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cigarette Smoke Extract Activates Hypoxia-Inducible Factors in a Reactive Oxygen Species-Dependent Manner in Stroma Cells from Human Endometrium2021

    • Author(s)
      Kida Naoko、Matsuo Yoshiyuki、Hashimoto Yoshiko、Nishi Kenichiro、Tsuzuki-Nakao Tomoko、Bono Hidemasa、Maruyama Tetsuo、Hirota Kiichi、Okada Hidetaka
    • Journal Title

      Antioxidants

      Volume: 10 Issue: 1 Pages: 48-48

    • DOI

      10.3390/antiox10010048

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Optogenetic regulation of embryo implantation in mice using photoactivatable CRISPR-Cas92020

    • Author(s)
      Takao Tomoka、Sato Moritoshi、Maruyama Tetsuo
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 117 Issue: 46 Pages: 28579-28581

    • DOI

      10.1073/pnas.2016850117

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] UDP-glucose, a cellular danger signal, and nucleotide receptor P2Y14 enhance the invasion of human extravillous trophoblast cells2020

    • Author(s)
      Katakura Satomi、Takao Tomoka、Arase Toru、Yoshimasa Yushi、Tomisato Shoko、Uchida Sayaka、Masuda Hirotaka、Uchida Hiroshi、Tanaka Mamoru、Maruyama Tetsuo
    • Journal Title

      Placenta

      Volume: 101 Pages: 194-203

    • DOI

      10.1016/j.placenta.2020.09.061

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 光応答性CRISPR/Cas9システムを用いたマウス子宮における胚着床のin vivo制御2020

    • Author(s)
      高尾知佳,升田博隆,佐藤守俊,丸山哲夫
    • Journal Title

      日本生殖内分泌学会雑誌

      Volume: 25 Pages: 17-20

    • Related Report
      2020 Annual Research Report
    • Open Access
  • [Journal Article] 【内膜症を極めるⅠ -内膜の機能と着床をめぐる最近の話題-】 子宮内膜の幹細胞と再生医学2020

    • Author(s)
      丸山哲夫
    • Journal Title

      産婦人科の実際

      Volume: 69 Pages: 1069-1074

    • Related Report
      2020 Annual Research Report
  • [Presentation] Identification and Characterization of Stem Cell-Like Cells in Endometriotic Lesions Using an Endometrial Mesenchymal Stem Cell Marker SUSD2.2023

    • Author(s)
      Shoko Tomisato, Tomoka Takao, Eiko Maki, Satomi Katakura, Yushi Yoshimasa,Hirotaka Masuda, Mamoru Tanaka, Kaori Koga, Yutaka Osuga, Tetsuo Maruyama
    • Organizer
      70th Annual Scientific Meeting of the Society for Reproductive Investigation
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 子宮内膜脱細胞化骨格は子宮内膜が全周性全層欠損した子宮の内膜間質部の再生を促進す る2023

    • Author(s)
      吉政 佑之、丸山 哲夫、髙尾 知佳、升田 博隆、片倉 慧美、富里 祥子、内田 明花、内田 浩、田中 守
    • Organizer
      第22回日本再生医療学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 免疫と疼痛の性差から子宮内膜症とその治療を考える2023

    • Author(s)
      丸山哲夫
    • Organizer
      第44回日本エンドメトリオーシス学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 子宮内膜脱細胞化骨格による子宮内膜の全層欠損の修復・再生の試み2022

    • Author(s)
      5.吉政佑之、丸山哲夫、高尾知佳、升田博隆、片倉慧美、富里祥子、内田明花、内田 浩、田中 守
    • Organizer
      第67回日本生殖医療学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 子宮内膜幹細胞マーカーSUSD2/W5C5を用いた子宮内膜症病変における幹細胞様細胞の同定と細胞特性の解析2022

    • Author(s)
      7.富里祥子,丸山哲夫,片倉慧美,吉政佑之,内田明花,内田 浩,升田博隆,青木大輔,田中 守,甲賀かをり,牧 瑛子,大須賀穣
    • Organizer
      第74回日本産科婦人科学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] [ランチョンセミナー] 性差とアンドロゲンから子宮内膜症の疼痛を考える2022

    • Author(s)
      丸山哲夫
    • Organizer
      第43回日本エンドメトリオーシス学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] マウスを用いた経済的エンハンサーRNA解析による卵巣体細胞特異的エンハンサー交付領域および疾患感受性領域の同定2022

    • Author(s)
      中川竜一,高澤 啓,我有茉希,辻(細川)敦美,川路英哉,村川泰裕,高田修治,三上剛史,鳴海覚志,深見真紀,丸山哲夫,林崎良英,森尾友宏,鹿島田健一
    • Organizer
      第26回日本生殖内分泌学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 子宮内膜症病巣における幹細胞マーカーSUSD2/W5C5陽性細胞の同定とその幹細胞特性の同定とその幹細胞特性の解析2021

    • Author(s)
      富里祥子,丸山哲夫,高尾知佳,片倉慧美,吉政佑之,内田明花,内田 浩,升田博隆,田中 守,甲賀かをり,大須賀穣
    • Organizer
      第66回日本生殖医学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] [JSOG Congress Encouragement Award] UDP-glucose, a celluar danger signal, promotes the invasion of human extravillous trophoblast cells via P2RY142021

    • Author(s)
      Satomi Katakura, Tetsuo Maruyama, Toru Arase, Yushi Yoshimasa, Shoko Tomisato, Sayaka Uchida, Hirotaka Masuda, Hiroshi Uchida, Mamoru Tanaka, Daisuke Aoki
    • Organizer
      第37回日本産科婦人科学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] [高得点演題] 子宮内膜脱細胞化骨格の移植は子宮内膜の全層欠損を修復する2020

    • Author(s)
      吉政佑之,丸山哲夫,升田博隆,内田 浩,内田明花,片倉慧美,富里祥子,田中 守,青木大輔
    • Organizer
      第72回日本産科婦人科学会(WEB開催)
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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