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Identification of the gene responsible for pulmonary fibrosis, and exploration about the association between cell death and fibrosis through the disease-derived iPS cell-differentiated lung cells

Research Project

Project/Area Number 20H03687
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Setoguchi Yasuhiro  東京医科歯科大学, 大学院医歯学総合研究科, 特任教授 (90206649)

Co-Investigator(Kenkyū-buntansha) 宮崎 泰成  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30396999)
後藤 慎平  京都大学, iPS細胞研究所, 教授 (50747219)
岡本 師  東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (60724200)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2022: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Keywords家族性間質性肺炎 / サーファクタント / 遺伝子 / エクソーム解析 / 小胞体ストレス / 細胞死 / iPS細胞 / 肺胞II型表皮細胞 / 肺線維症 / 遺伝性間質性肺炎 / トランスクリプトーム解析 / iPS / 肺オルガノイド / 肺線維化 / サーファクタント蛋白遺伝子 / 細胞老化 / ネクロプトーシス / トランスクリプトーム / テロメア / エクソーム / 線維性間質性肺炎 / 網羅的エクソーム解析 / サーファクタント関連遺伝子 / ネクロトーシス / RNA sequence / 線維性間質生肺炎 / 遺伝子変異 / apoptosis / necroptosis
Outline of Research at the Start

Surfactant関連遺伝子において肺胞上皮細胞死はapoptosisだけでなく新たな細胞死necroptosisが関与することを証明した。肺線維化責任遺伝子変異においてERストレスを介するapoptosisとnecroptosisの分岐はどのような機序で起こっているのか各遺伝子変異を有する症例から作成したiPS細胞を分化させた肺線維症特異的肺構成細胞を用いsingle cell transcriptome等で解析し治療法開発までの応用を考慮した研究である。

Outline of Final Research Achievements

To investigate the causes of familial interstitial lung disease, we identified the surfactant protein A (SFTPA) and C (SFTPC) genes. We found that mutations in these genes induce two different types of cell death, necroptosis and apoptosis, in type II alveolar epithelial cells. By developing a system to quantify ER stress, we discovered that the level of stress varies according to genetic mutations and that this can affect clinical pathology. In addition, the study showed that lung epithelial cells derived from iPS cells created from the peripheral blood of each patient have the potential to be analysed as an alternative to cells obtained from lung biopsies. It may be useful for the development of therapeutic drugs to quantify ER stress and disease-derived iPS cells.

Academic Significance and Societal Importance of the Research Achievements

ER stressの定量化システムによってSFTPA1/A2, SFTPCの変異によってER stressの違いがあることを明らかにし、ER stressによる細胞死の種類が異なることは新規の知見である。肺線維症においてER stressは遺伝子変異にかかわらず認められることも考え合わせるとER stressの定量化は、治療候補薬物の大規模スクリーニングへの応用が可能となる。また、患者由来iPS細胞からの各種肺細胞への分化誘導が可能となり線維化発症の機序解明だけでなくER stress定量化システムとの併用で間質性肺疾患のprecision medicine構築も可能となる意義がある。

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

    (33 results)

All 2023 2022 2021 2020 Other

All Journal Article (21 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 19 results,  Open Access: 10 results) Presentation (9 results) (of which Invited: 3 results) Book (1 results) Remarks (2 results)

  • [Journal Article] Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of SFTPC2023

    • Author(s)
      Motoyasu Hosokawa, Ryuta Mikawa, Atsuko Hagiwara, Yukiko Okuno, Tomonari Awaya, Yuki Yamamoto, Senye Takahashi, Haruka Yamaki, Mitsujiro Osawa, Yasuhiro Setoguchi, Megumu K Saito, Shinji Abe, Toyohiro Hirai, Shimpei Gotoh, Masatoshi Hagiwara
    • Journal Title

      iScience

      Volume: 26 Issue: 10 Pages: 107731-107731

    • DOI

      10.1016/j.isci.2023.107731

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ACE2 knockout hinders SARS-CoV-2 propagation in iPS cell-derived airway and alveolar epithelial cells2023

    • Author(s)
      Niwa Ryo、Sakai Kouji、Lung Mandy Siu Yu、Matsumoto Tomoko、Mikawa Ryuta、Maehana Shotaro、Suzuki Masato、Yamamoto Yuki、Maurissen Thomas L.、Hirabayashi Ai、Noda Takeshi、Kubo Makoto、Gotoh Shimpei、Woltjen Knut
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 11 Pages: 1290876-1290876

    • DOI

      10.3389/fcell.2023.1290876

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characteristic genetic spectrum of primary ciliary dyskinesia in Japanese patients and global ethnic heterogeneity: population-based genomic variation database analysis2023

    • Author(s)
      Xu Y, Feng G, Yano T, Masuda S, Nagao M, Gotoh S, Ikejiri M, Tanabe M, Takeuchi K.
    • Journal Title

      J Hum Genet .

      Volume: 68 Issue: 7 Pages: 455-461

    • DOI

      10.1038/s10038-023-01142-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Muc5b plays a role in the development of inflammation and fibrosis in hypersensitivity pneumonitis induced by<i>Saccharopolyspora rectivirgula</i>2022

    • Author(s)
      Okamoto Tsukasa、Dobrinskikh Evgenia、Hennessy Corinne E.、Liu Naoko、Schwarz Marvin I.、Evans Christopher M.、Fontenot Andrew P.、Yang Ivana V.、Schwartz David A.
    • Journal Title

      American Journal of Physiology-Lung Cellular and Molecular Physiology

      Volume: 323 Issue: 3 Pages: L329-L337

    • DOI

      10.1152/ajplung.00061.2022

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] iPSC-derived mesenchymal cells that support alveolar organoid development2022

    • Author(s)
      Tamai Koji、Sakai Kouji、Yamaki Haruka、Moriguchi Keita、Igura Koichi、Maehana Shotaro、Suezawa Takahiro、Takehara Kazuaki、Hagiwara Masatoshi、Hirai Toyohiro、Gotoh Shimpei
    • Journal Title

      Cell Reports Methods

      Volume: 2 Issue: 10 Pages: 100314-100314

    • DOI

      10.1016/j.crmeth.2022.100314

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Perspectives of future lung toxicology studies using human pluripotent stem cells2022

    • Author(s)
      Masui Atsushi、Hirai Toyohiro、Gotoh Shimpei
    • Journal Title

      Archives of Toxicology

      Volume: 96 Issue: 2 Pages: 389-402

    • DOI

      10.1007/s00204-021-03188-9

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of serum surfactant protein-D as a prognostic predictor in fibrotic hypersensitivity pneumonitis.2022

    • Author(s)
      Ejima M, Okamoto T, Suzuki T, Miyazaki Y
    • Journal Title

      Respiratory investigation

      Volume: 60 Issue: 3 Pages: 369-378

    • DOI

      10.1016/j.resinv.2021.12.003

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Successful diagnosis of humidifier lung by individual provocation test to a responsible environment, a case report2022

    • Author(s)
      Murakami T、Iijima Y、Ando T、Ejima M、Shirai Tsuyoshi、Furusawa H、Okamoto T、Tateishi T、Tamaoka M、Miyazaki Y
    • Journal Title

      Respiratory Medicine Case Reports

      Volume: 37 Pages: 101639-101639

    • DOI

      10.1016/j.rmcr.2022.101639

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] びまん性肺疾患 家族性間質性肺炎の臨床と遺伝子変異2022

    • Author(s)
      瀬戸口靖弘
    • Journal Title

      日本臨床

      Volume: 80 Pages: 1415-1424

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Alternative gene expression by TOLLIP variant is associated with lung function in chronic hypersensitivity pneumonitis.2021

    • Author(s)
      Katayanagi S, Setoguchi Y, Kitagawa S, Okamoto T, Miyazaki Y
    • Journal Title

      Chest

      Volume: 161 Issue: 2 Pages: 458-469

    • DOI

      10.1016/j.chest.2021.08.052

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) Is Elevated in Patients with Asthma and Airway Obstruction2021

    • Author(s)
      Kawagoe Junichiro、Kono Yuta、Togashi Yuki、Ishiwari Mayuko、Toriyama Kazutoshi、Yajima Chika、Nakayama Hideaki、Kasagi Satoshi、Abe Shinji、Setoguchi Yasuhiro
    • Journal Title

      Current Medical Science

      Volume: 41 Issue: 2 Pages: 323-328

    • DOI

      10.1007/s11596-021-2350-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Disease modeling of pulmonary fibrosis using human pluripotent stem cell-derived alveolar organoids2021

    • Author(s)
      Suezawa Takahiro、Kanagaki Shuhei、Moriguchi Keita、Masui Atsushi、Nakao Kazuhisa、Toyomoto Masayasu、Tamai Koji、Mikawa Ryuta、Hirai Toyohiro、Murakami Koji、Hagiwara Masatoshi、Gotoh Shimpei
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 12 Pages: 2973-2987

    • DOI

      10.1016/j.stemcr.2021.10.015

    • NAID

      120007177809

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Modeling of lung phenotype of Hermansky?Pudlak syndrome type I using patient-specific iPSCs2021

    • Author(s)
      Suezawa Takahiro、Kanagaki Shuhei、Korogi Yohei、Nakao Kazuhisa、Hirai Toyohiro、Murakami Koji、Hagiwara Masatoshi、Gotoh Shimpei
    • Journal Title

      Respiratory Research

      Volume: 22 Issue: 1 Pages: 1-13

    • DOI

      10.1186/s12931-021-01877-8

    • NAID

      120007169957

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells2021

    • Author(s)
      Yin Xin、Riva Laura、Pu Yuan、Martin-Sancho Laura、Kanamune Jun、Yamamoto Yuki、Sakai Kouji、Gotoh Shimpei、Miorin Lisa、De Jesus Paul D.、Yang Chih-Cheng、Herbert Kristina M.、Yoh Sunnie、Hultquist Judd F.、Garc?a-Sastre Adolfo、Chanda Sumit K.
    • Journal Title

      Cell Reports

      Volume: 34 Issue: 2 Pages: 108628-108628

    • DOI

      10.1016/j.celrep.2020.108628

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] IL-17A-Secreting Memory γδ T Cells Play a Pivotal Role in Sensitization and Development of Hypersensitivity Pneumonitis.2021

    • Author(s)
      Takashi Yamana, Tsukasa Okamoto, Masahiro Ishizuka, Satoshi Hanzawa, Masaru Ejima, Sho Shibata, Yasunari Miyazaki
    • Journal Title

      Journal of immunology

      Volume: 206 Issue: 2 Pages: 355-365

    • DOI

      10.4049/jimmunol.2000198

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling2021

    • Author(s)
      Gally Fabienne、Sasse Sarah K.、Kurche Jonathan S.、Gruca Margaret A.、Cardwell Jonathan H.、Okamoto Tsukasa、Chu Hong W.、Hou Xiaomeng、Poirion Olivier B.、Buchanan Justin、Preissl Sebastian、Ren Bing、Colgan Sean P.、Dowell Robin D.、Yang Ivana V.、Schwartz David A.、Gerber Anthony N.
    • Journal Title

      JCI Insight

      Volume: 6 Issue: 2

    • DOI

      10.1172/jci.insight.144294

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The risk of interstitial lung disease during biological treatment in Japanese patients with psoriasis2020

    • Author(s)
      Matsumoto Y.、Abe N.、Tobita R.、Kawakami H.、Nakayama H.、Setoguchi Y.、Tsuboi R.、Okubo Y.
    • Journal Title

      Clinical and Experimental Dermatology

      Volume: 45 Issue: 7 Pages: 853-858

    • DOI

      10.1111/ced.14259

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A case of imatinib-related obstructive bronchiolitis followed long term2020

    • Author(s)
      Yajima Chika、Kokuho Nariaki、Toriyama Kazutoshi、Kawagoe Junichiro、Togashi Yuki、Matsubayashi Jun、Nakayama Hideaki、Setoguchi Yasuhiro、Abe Shinji
    • Journal Title

      Respiratory Medicine Case Reports

      Volume: 30 Pages: 101052-101052

    • DOI

      10.1016/j.rmcr.2020.101052

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Changes in serum KL-6 levels during short-term strict antigen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumonitis caused by avian antigens2020

    • Author(s)
      Hanzawa Satoshi、Tateishi Tomoya、Ishizuka Masahiro、Inoue Yukihisa、Honda Takayuki、Kawahara Tatsuo、Tomita Makoto、Miyazaki Yasunari
    • Journal Title

      Respiratory Investigation

      Volume: 58 Issue: 6 Pages: 457-464

    • DOI

      10.1016/j.resinv.2020.05.007

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Directed induction of alveolar type I cells derived from pluripotent stem cells via Wnt signaling inhibition2020

    • Author(s)
      Kanagaki Shuhei、Ikeo Satoshi、Suezawa Takahiro、Yamamoto Yuki、Seki Masahide、Hirai Toyohiro、Hagiwara Masatoshi、Suzuki Yutaka、Gotoh Shimpei
    • Journal Title

      STEM CELLS

      Volume: 39 Issue: 2 Pages: 156-169

    • DOI

      10.1002/stem.3302

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic Hypersensitivity Pneumonitis, an Interstitial Lung Disease with Distinct Molecular Signatures2020

    • Author(s)
      Furusawa Haruhiko、Cardwell Jonathan H.、Okamoto Tsukasa、Walts Avram D.、Konigsberg Iain R.、Kurche Jonathan S.、Bang Tami J.、Schwarz Marvin I.、Brown Kevin K.、Kropski Jonathan A.、Rojas Mauricio、Cool Carlyne D.、Lee Joyce S.、Wolters Paul J.、Yang Ivana V.、Schwartz David A.
    • Journal Title

      American Journal of Respiratory and Critical Care Medicine

      Volume: 202 Issue: 10 Pages: 1430-1444

    • DOI

      10.1164/rccm.202001-0134oc

    • Related Report
      2020 Annual Research Report
  • [Presentation] SFTPA1/SFTPA2変異を有する間質性肺炎の臨床像と分子病態の特徴2023

    • Author(s)
      瀬戸口 靖弘, 島村 貴史, 伊藤 優, 片柳 真司, 宮崎 泰成
    • Organizer
      第61回日本呼吸器学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 間質性肺炎の発症機序,進展を探る2023

    • Author(s)
      瀬戸口 靖弘
    • Organizer
      第61回日本呼吸器学会学術総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] SFTPA1/SFTPA2変異を有する間質性肺炎の臨床像と病態2023

    • Author(s)
      瀬戸口 靖弘, 片柳 真司, 宮崎 泰成
    • Organizer
      日本界面医学会学術総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Telomerase関連遺伝子変異を有するPF-ILDの臨床的特徴2022

    • Author(s)
      瀬戸口靖弘
    • Organizer
      第62回日本呼吸器学会学術講演会
    • Related Report
      2022 Annual Research Report
  • [Presentation] SFTPA1/SFTPA2変異を有する間質生肺炎の臨床像と病態2022

    • Author(s)
      瀬戸口靖弘
    • Organizer
      第58回 肺サーファクタント・界面医学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 過敏性肺炎における免疫反応と線維化2022

    • Author(s)
      宮崎泰成
    • Organizer
      第58回 肺サーファクタント・界面医学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 肺線維化進展の機序はどこまで明らかになってきたか2021

    • Author(s)
      瀬戸口靖弘
    • Organizer
      日本肺サーファクタント・界面医学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 本邦の慢性過敏性肺炎におけるMUC5Bプロモーター多型の特徴と拘束性障害の進展の検討2021

    • Author(s)
      片柳 真司, 岡本 師, 瀬戸口 靖弘, 宮崎 泰成
    • Organizer
      日本肺サーファクタント・界面医学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] TOLLIP rs5743899は慢性過敏性肺炎における肺線維化の予測因子となる可能性がある2021

    • Author(s)
      片柳 真司, 瀬戸口 靖弘, 岡本 師, 宮崎 泰成
    • Organizer
      日本アレルギー学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Book] 内科学 第12版 (嚢胞性線維症、原発性繊毛機能不全症)2022

    • Author(s)
      瀬戸口靖弘  矢﨑 義雄、小室 一成編
    • Total Pages
      2572
    • Publisher
      朝倉書店
    • ISBN
      9784254322804
    • Related Report
      2022 Annual Research Report
  • [Remarks] 疾患特異的iPS細胞を用いて遺伝性間質性肺炎の治療薬の候補化合物を発見

    • URL

      https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/230913-150001.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 慢性過敏性肺炎における肺の線維化に関わる遺伝子を発見

    • URL

      https://www.tmd.ac.jp/press-release/20210826-1/

    • Related Report
      2021 Annual Research Report

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

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