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Investigating the role of mucin in pulmonary fibrosis-associated microbiota dysbiosis using MUC5B overexpressing mice

Research Project

Project/Area Number 20K08564
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionMie University

Principal Investigator

Gabazza Esteban  三重大学, 医学系研究科, 教授 (00293770)

Co-Investigator(Kenkyū-buntansha) 戸田 雅昭  三重大学, 医学系研究科, 講師 (10202201)
竹下 敦郎  三重大学, 医学系研究科, 助教 (10830490)
安間 太郎  三重大学, 医学系研究科, 助教 (80773887)
小林 哲  三重大学, 医学部附属病院, 准教授 (20437114)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords細菌叢 / 細胞死 / corisin / 肺線維症 / ムチン / MUC5B / 抗線維化剤 / 予後 / 急性増悪 / 肺内細菌叢 / 細胞死因子 / TGFbeta1 / 抗コリシン抗体 / トランスジェニックマウス / MUC5Bタンパク / TGFΒ1 / アポトーシス / 細胞死誘導因子 / 急性肺障害 / コリシン / 成長因子 / ブレオマイシン / ムチン過剰発現 / 肺疾患
Outline of Research at the Start

肺内細菌叢とMUC5B遺伝子の単塩基多型であるrs35705950は特発性肺線維症の病態形成に関与していることが示されているが、その機序は未だ不明である。本研究の目的はヒトMUC5Bの単塩基多型の過剰発現マウスを用いて肺線維症マウスモデルを作製し、in vivo 実験によってMUC5Bの過剰発現による肺内細菌叢のアンバランスが肺線維症の病態形成に関与するかを検討する。さらに、肺特異的ヒトTGF-beta1とMUC5Bの単塩基多型の遺伝子系を有する二重トランスジェニックマウスにおいてもMUC5Bの過剰発現による肺内細菌叢のアンバランスが肺線維症の発症機序に関与するかを検討する。

Outline of Final Research Achievements

Genome-wide linkage study has shown that patients with a single nucleotide polymorphism (rs35705950) of MUC5B have a 20-fold increased risk of developing idiopathic pulmonary fibrosis. Recently, it has been reported that microbiota dysbiosis in the lungs is involved in the progression of idiopathic pulmonary fibrosis. Therefore, in this study, we used MUC5B overexpression transgenic (TG) mice and wild-type mice to examine the characteristics of microbiota in the lungs and its involvement in the pathogenesis of pulmonary fibrosis. As a result, we found that the expression of corisin, a microbiota-derived cell death inducer, was high in MUC5B-TG mice and wild-type mice with pulmonary fibrosis and that it was involved in the promotion of inflammation and the pathogenesis of pulmonary fibrosis. Furthermore, we also found that anti-corisin monoclonal antibody had an inhibitory effect on pulmonary fibrosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、肺線維症マウスモデルを用いて、細菌由来細胞死誘導ペプチドが肺線維症の病態形成に関与することと抗corisinモノクローナル中和抗体が治療薬として有効であることを明らかにした。本研究で得た結果は抗肺線維化剤の開発につながる可能性があり、社会的意義が高いと考えられる。

Report

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

    (22 results)

All 2023 2022 2021 2020

All Journal Article (11 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 11 results,  Open Access: 9 results) Presentation (11 results)

  • [Journal Article] Inhibition of a Microbiota-Derived Peptide Ameliorates Established Acute Lung Injury2023

    • Author(s)
      D'Alessandro Fridman V, D'Alessandro-Gabazza CN, Yasuma T, Toda M, Takeshita A, Tomaru A, Tharavecharak S, Lasisi IO, Hess RY, Nishihama K, Fujimoto H, Kobayashi T, Cann I, Gabazza EC.
    • Journal Title

      American Journal of Pathology

      Volume: 23 Issue: 6 Pages: 740-754

    • DOI

      10.1016/j.ajpath.2023.03.003

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Is Helicobacter pylori infection inversely correlated with atopic, skin, and autoimmune diseases?2022

    • Author(s)
      Yasuma T, D'Alessandro-Gabazza CN, Fujimoto H, Kobayashi T, Imoto I, Gabazza EC.
    • Journal Title

      Allergy

      Volume: 77 Issue: 10 Pages: 3165-3166

    • DOI

      10.1111/all.15306

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Complete Genome Sequences of Three Staphylococcus haemolyticus Strains Isolated from the Lung of a TGFβ1 Transgenic Mouse with Lung Fibrosis2022

    • Author(s)
      Abdel-Hamid AM, D'Alessandro-Gabazza CN, Yasuma T, Walden KKO, Fields CJ, Gabazza EC, Cann I.
    • Journal Title

      Microbiology Resource Announcements

      Volume: 11 Issue: 4

    • DOI

      10.1128/mra.01176-21

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Correlation of total serum HDL particles with a predictor of mortality risk in idiopathic pulmonary fibrosis2022

    • Author(s)
      Yasuma T, D'Alessandro-Gabazza CN, Fujimoto H, Kobayashi T, Gabazza EC.
    • Journal Title

      European Respiratory Journal

      Volume: 59 Issue: 4 Pages: 2103175-2103175

    • DOI

      10.1183/13993003.03175-2021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Inhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis.2022

    • Author(s)
      D'Alessandro-Gabazza CN, Yasuma T, Kobayashi T, Toda M, Abdel-Hamid AM, Fujimoto H, Hataji O, Nakahara H, Takeshita A, Nishihama K, Okano T, Saiki H, Okano Y, Tomaru A, D'Alessandro VF, Shiraishi M, Mizoguchi A, Ono R, Ohtsuka J, Fukumura M, Nosaka T, et al. & Gabazza EC
    • Journal Title

      Nat Commun

      Volume: 13 Issue: 1 Pages: 1558-1558

    • DOI

      10.1038/s41467-022-29064-3

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Response of Lung Microbiota to Changes of Pulmonary Innate Immunity under Healthy Conditions2022

    • Author(s)
      Yasuma Taro、D’Alessandro-Gabazza Corina N.、Fujimoto Hajime、Kobayashi Tetsu、Gabazza Esteban C.
    • Journal Title

      American Journal of Respiratory and Critical Care Medicine

      Volume: 205 Issue: 4 Pages: 477-477

    • DOI

      10.1164/rccm.202109-2187le

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Potential of Digital Polymerase Chain Reaction for Improving Diagnostic Yield of Nontuberculous Mycobacteria Pulmonary Disease2021

    • Author(s)
      Nishii Yoichi、Furuhashi Kazuki、Nakamura Saki、Nishio Miho、Nakamura Yuki、Ushiro Kengo、Ito Kentaro、Sakaguchi Tadashi、Suzuki Yuta、Fujiwara Kentaro、Yasuma Taro、Kobayashi Tetsu、D'Alessandro-Gabazza Corina、Gabazza Esteban C、Taguchi Osamu、Hataji Osamu
    • Journal Title

      Infection and Drug Resistance

      Volume: Volume 14 Pages: 5079-5087

    • DOI

      10.2147/idr.s338165

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Microbiome-Derived Peptide Induces Apoptosis of Cells from Different Tissues2021

    • Author(s)
      Saiki Haruko、Okano Yuko、Yasuma Taro、Toda Masaaki、Takeshita Atsuro、Abdel-Hamid Ahmed M.、Fridman D’Alessandro Valeria、Tsuruga Tatsuki、D’Alessandro-Gabazza Corina N.、Katayama Kan、Sugimoto Masahiko、Fujimoto Hajime、Yamanaka Keiichi、Kobayashi Tetsu、Cann Isaac、Gabazza Esteban C.
    • Journal Title

      Cells

      Volume: 10 Issue: 11 Pages: 2885-2885

    • DOI

      10.3390/cells10112885

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Degradation of complex arabinoxylans by human colonic Bacteroidetes2021

    • Author(s)
      Pereira Gabriel V.、Abdel-Hamid Ahmed M.、Dutta Soumajit、D’Alessandro-Gabazza Corina N.、Wefers Daniel、Farris Jacob A.、Bajaj Shiv、Wawrzak Zdzislaw、Atomi Haruyuki、Mackie Roderick I.、Gabazza Esteban C.、Shukla Diwakar、Koropatkin Nicole M.、Cann Isaac
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1

    • DOI

      10.1038/s41467-020-20737-5

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Too Premature to Deny the Potential of Thrombomodulin-alfa in Idiopathic Pulmonary Fibrosis2020

    • Author(s)
      Kobayashi Tetsu、Hataji Osamu、Fujimoto Hajime、D'Alessandro-Gabazza Corina、Yasuma Taro、Gabazza Esteban C
    • Journal Title

      American Journal of Respiratory and Critical Care Medicine

      Volume: - Issue: 11 Pages: 1449-1450

    • DOI

      10.1164/rccm.202002-0271le

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Low-Dose of Intrapulmonary Pirfenidone Improves Human Transforming Growth Factorβ1-Driven Lung Fibrosis2020

    • Author(s)
      Okano Tomohito、Kobayashi Tetsu、Yasuma Taro、D’Alessandro-Gabazza Corina N.、Toda Masaaki、Fujimoto Hajime、Nakahara Hiroki、Okano Yuko、Takeshita Atsuro、Nishihama Kota、Saiki Haruko、Tomaru Atsushi、Fridman D’Alessandro Valeria、Ishida Satoru、Sugimoto Hiromi、Takei Yoshiyuki、Gabazza Esteban C.
    • Journal Title

      Frontiers in Pharmacology

      Volume: 11

    • DOI

      10.3389/fphar.2020.593620

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 肺線維症モデルマウスにおける肺内細菌叢の検討2022

    • Author(s)
      藤本 源、小林 哲、ガバザ エステバン
    • Organizer
      第71回日本アレルギー学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ブドウ球菌由来のアポトーシス促進ペプチドはブレオマイシン誘発肺線維症モデルにおいて慢性期の肺線維化を促進する2022

    • Author(s)
      岡野 智仁、Valeria Fridman D’Alessandro、古橋 一樹、大岩 綾香、鶴賀 龍樹、齋木 晴子、藤原 拓海、浅山 健太郎、高橋 佳紀、都丸 敦史、中原 博紀、藤本 源、岡野 優子、竹下 敦郎、安間 太郎、Corina N. D’Alessandro-Gabazza、Esteban C. Gabazza、小林 哲
    • Organizer
      第62回日本呼吸器学会学術講演会
    • Related Report
      2022 Annual Research Report
  • [Presentation] マトリックスメタロプロテアーゼ-2(MMP-2)の肺線維症への役割2022

    • Author(s)
      鶴賀 龍樹、小林 哲、齋木 晴子、岡野 智仁、藤原 拓海、浅山 健太郎、都丸 敦史、高橋 佳紀、藤本 源、Corina N. D’Alessandro-Gabazza、Esteban C. Gabazza
    • Organizer
      第62回日本呼吸器学会学術講演会
    • Related Report
      2022 Annual Research Report
  • [Presentation] The Role of the Lung Microbiota in Acute Exacerbation of Pulmonary Fibrosis2022

    • Author(s)
      Valeria Fridman D’Alessandro, Tomohito Okano, Haruko Saiki, Tatsuki Tsuruga, Kentaro Asayama, Atsushi Tomaru, Hiroki Nakahara, Hajime Fujimoto, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza, Tetsu Kobayashi
    • Organizer
      第62回日本呼吸器学会学術講演会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Amelioration of kidney fibrosis and dysfunction by recombinant thrombomodulin2021

    • Author(s)
      Asturo Takeshita, Taro Yasuma, Yuko Okano, Kota Nishihama, Valeria Fridman D'Alessandro, Masaaki Toda, Corina N. D'Alessandro-Gabazza, Yutaka Yano, Esteban C. Gabazza
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] A microbiome-derived peptide induces apoptosis of cells from different tissues2021

    • Author(s)
      Yuko Okano1, Atsuro Takeshita, Kota Nishihama, Valeria Fridman, Taro Yasuma, Corina Gabazza, Masaaki Toda, Yutaka Yano, Esteban Gabazza
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Thrombomodulin suppresses apoptosis of podocytes by activating Akt signal pathway2021

    • Author(s)
      Valeria Fridman D'Alessandro, Taro Yasuma, Masaaki Toda, Atsuro Takeshita, Corina D'Alessandro Gabazza, Yuko Okano, Yutaka Yano, Esteban Gabazza
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 抗甲状腺薬によるANCA関連間質性肺炎と考えられた1例2020

    • Author(s)
      岡野 智仁、鶴賀 龍樹、齊木 晴子、藤原 拓海、浅山 健太郎、高橋 佳紀、都丸 敦史、中原 博紀、藤本 源、小林 哲、ガバザ エステバン
    • Organizer
      第117回日本呼吸器学会東海地方会
    • Related Report
      2020 Research-status Report
  • [Presentation] TGF-Β1過剰発現マウスを用いた肺線維化と発癌に関する検討2020

    • Author(s)
      中原 博紀、小林 哲、齊木 晴子、藤原 拓海、岡野 智仁、浅山 健太郎、都丸 敦史、高橋 佳紀、藤本 源、ガバザ コリナ、ガバザ エステバン
    • Organizer
      第60回日本呼吸器学会学術講演会
    • Related Report
      2020 Research-status Report
  • [Presentation] MUC5Bのrs35705950単塩基多型過剰発現トランスジェニックマウスの作製2020

    • Author(s)
      都丸 敦史、小林 哲、齊木 晴子、浅山 健太郎、岡野 智仁、藤原 拓海、高橋 佳紀、中原 博紀、藤本 源、ガバザ エステバン
    • Organizer
      第60回日本呼吸器学会学術講演会
    • Related Report
      2020 Research-status Report
  • [Presentation] The Role of Matrix Metalloproteinase-2 in Pulmonary Fibrosis2020

    • Author(s)
      Tomohito Okano, Tetsu Kobayashi, Haruko Saiki, Takumi Fujiwara, Kentaro Asayama, Yoshinori Takahashi, Atsushi Tomaru, Hiroki Nakahara, Hajime Fujimoto, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza
    • Organizer
      第60回日本呼吸器学会学術講演会
    • Related Report
      2020 Research-status Report

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

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