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New mouse model of rare lung disease and novel therapy with macrophages

Research Project

Project/Area Number 16K21750
Research Category

Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)

Allocation TypeMulti-year Fund
Research Field Respiratory organ internal medicine
Research InstitutionJichi Medical University

Principal Investigator

SUZUKI Takuji  自治医科大学, 医学部, 准教授 (80344670)

Project Period (FY) 2017 – 2019
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥32,760,000 (Direct Cost: ¥25,200,000、Indirect Cost: ¥7,560,000)
Keywords呼吸器疾患 / 肺胞蛋白症 / ノックアウトマウス / マクロファージ / iPS細胞
Outline of Final Research Achievements

Hereditary pulmonary alveolar proteinosis (hPAP) is rare genetic diseases caused by GM-CSF receptor alpha or beta gene (CSF2RA or CSF2RB, respectively) mutation. hPAP with CSF2RA gene mutation has been difficult to study due to the unavailability of a mouse model with Csf2ra gene mutation. We demonstrated the Csf2ra gene deficient mice are the faithful model of human hPAP with CSF2RA gene mutations. The characteristics of the Csf2ra gene deficient mice including lung histology, macrophage phenotype and function, bronchoalveolar lavage fluid appearance, gene expression profiles and PAP biomarkers showed similar abnormality as hPAP patients with CSF2RA gene mutations. We also demonstrated that pulmonary macrophage transplantation therapy is effective and safe in Csf2ra gene deficient mice. These results strongly support the potential utility of the new disease model mice and the feasibility of novel cell therapy for the patients with this specific genetic lung disease.

Academic Significance and Societal Importance of the Research Achievements

これまで存在しなかったヒトCSF2RA遺伝子変異による遺伝性肺胞蛋白症の有効な疾患モデルが確立されたことで、その病態解析および生物学的解析を行えるという学術的意義がある。また、新規治療法の開発といったトランスレーショナルな研究を行うことにより、患者さんへ治療法を還元していくという社会的意義がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report

Research Products

(26 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (6 results) Journal Article (12 results) (of which Int'l Joint Research: 11 results,  Peer Reviewed: 12 results,  Open Access: 11 results) Presentation (8 results) (of which Int'l Joint Research: 6 results,  Invited: 3 results)

  • [Int'l Joint Research] Cincinnati Children's Hospital Medical Center(アメリカ合衆国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Hannover Medical Center(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Cincinnati Children's Hospital Medical Center(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Hannover Medical Center(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Cincinnati Children's Hospital Medical Center(米国)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Hannover Medical Center(ドイツ)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Characteristics of 68 patients with clinically proven sarcoidosis based on the Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 criteria.2020

    • Author(s)
      Yamanouchi Y, Sawahata M, Sakamoto N, Hisata S, Shijubo N, Konno S, Yamaguchi T, Watanabe M, Kawashima H, Suzuki T, Bando M, Hagiwara K
    • Journal Title

      Respir Investig.

      Volume: 58 Pages: 102-109

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased Pulmonary GM-CSF Causes Alveolar Macrophage Accumulation. Mechanistic Implications for Desquamative Interstitial Pneumonitis2020

    • Author(s)
      Suzuki T, McCarthy C, Carey BC, Borchers M, Beck D, Wikenheiser- Brokamp KA, Black D, Chalk C, Trapnell BC
    • Journal Title

      Am J Respir Cell Mol Biol.

      Volume: 62 Pages: 87-94

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis2019

    • Author(s)
      Hetzel Miriam、Lopez-Rodriguez Elena、Mucci Adele、Nguyen Ariane Hai Ha、Suzuki Takuji、Shima Kenjiro、Buchegger Theresa、Dettmer Sabine、Rodt Thomas、Bankstahl Jens P.、Malik Punam、Knudsen Lars、Schambach Axel、Hansen Gesine、Trapnell Bruce C.、Lachmann Nico、Moritz Thomas
    • Journal Title

      Haematologica

      Volume: 105 Issue: 4 Pages: 1147-1157

    • DOI

      10.3324/haematol.2018.214866

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Long-Term Safety and Efficacy of Gene-Pulmonary Macrophage Transplantation Therapy of PAP in Csf2ra?/? Mice2019

    • Author(s)
      Arumugam Paritha、Suzuki Takuji、Shima Kenjiro、McCarthy Cormac、Sallese Anthony、Wessendarp Matthew、Ma Yan、Meyer Johann、Black Diane、Chalk Claudia、Carey Brenna、Lachmann Nico、Moritz Thomas、Trapnell Bruce C.
    • Journal Title

      Molecular Therapy

      Volume: 27 Issue: 9 Pages: 1597-1611

    • DOI

      10.1016/j.ymthe.2019.06.010

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Interferon-β Improves Sepsis-related Alveolar Macrophage Dysfunction and Post-septic ARDS-related Mortality2018

    • Author(s)
      Hiruma Takahiro、Tsuyuzaki Hitoshi、Uchida Kanji、Trapnell Bruce C、Yamamura Yoshiro、Kusakabe Yoshiomi、Totsu Tokie、Suzuki Takuji、Morita Shigeki、Doi Kent、Noiri Eisei、Nakamura Kensuke、Nakajima Susumu、Yahagi Naoki、Morimura Naoto、Chang Kyungho、Yamada Yoshitsugu
    • Journal Title

      American Journal of Respiratory Cell and Molecular Biology

      Volume: 印刷中 Issue: 1 Pages: 45-55

    • DOI

      10.1165/rcmb.2017-0261oc

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Use of low-cost three-dimensional printer to simulate grasping of bronchial foreign body2018

    • Author(s)
      Nakayama M, Yamamoto S, Kaneko N, Mato N, Suzuki T, Hagiwara K.
    • Journal Title

      Respirol Case Rep.

      Volume: 6 Issue: 7

    • DOI

      10.1002/rcr2.351

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pulmonary Transplantation of Human Induced Pluripotent Stem Cell-derived Macrophages Ameliorates Pulmonary Alveolar Proteinosis.2018

    • Author(s)
      Happle C, Lachmann N, Ackermann M, Mirenska A, Göhring G, Thomay K, Mucci A, Hetzel M, Glomb T, Suzuki T, Chalk C, Glage S, Dittrich-Breiholz O, Trapnell B, Moritz T, Hansen G.
    • Journal Title

      Am J Respir Crit Care Med.

      Volume: 198 Issue: 3 Pages: 350-360

    • DOI

      10.1164/rccm.201708-1562oc

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis.2018

    • Author(s)
      McCarthy C, Lee E, Bridges JP, Sallese A, Suzuki T, Woods JC, Bartholmai BJ, Wang T, Chalk C, Carey BC, Arumugam P, Shima K, Tarling EJ, Trapnell BC.
    • Journal Title

      Nat Commun.

      Volume: 9 Issue: 1 Pages: 3127-3127

    • DOI

      10.1038/s41467-018-05491-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice.2018

    • Author(s)
      Mucci A, Lopez-Rodriguez E, Hetzel M, Liu S, Suzuki T, Happle C, Ackermann M, Kempf H, Hillje R, Kunkiel J, Janosz E, Brennig S, Glage S, Bankstahl JP, Dettmer S, Rodt T, Gohring G, Trapnell B, Hansen G, Trapnell C, Knudsen L, Lachmann N, Moritz T.
    • Journal Title

      Stem Cell Reports.

      Volume: 11 Issue: 3 Pages: 696-710

    • DOI

      10.1016/j.stemcr.2018.07.006

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Targeting cholesterol homeostasis in lung diseases.2017

    • Author(s)
      Sallese A, Suzuki T, McCarthy C, Bridges J, Filuta A, Arumugam P, Shima K, Ma Y, Wessendarp M, Black D, Chalk C, Carey B, Trapnell BC.
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 10211-10211

    • DOI

      10.1038/s41598-017-10879-w

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages.2017

    • Author(s)
      Kong F, Liu Z, Jain VG, Shima K, Suzuki T, Muglia LJ, Starczynowski DT, Pasare C, Bhattacharyya S.
    • Journal Title

      The Journal of Immunology

      Volume: 199 Pages: 3654-3667

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Function and Safety of Lentivirus-Mediated Gene Transfer for CSF2RA-Deficiency.2017

    • Author(s)
      Hetzel M**, Suzuki T**, Hashtchin AR, Arumugam P, Carey B, Schwabbauer M, Kuhn A, Meyer J, Schambach A, Van Der Loo J, Moritz T, Trapnell BC, Lachmann N. (** : These authors are equally contributed.)
    • Journal Title

      Human Gene Therapy Methods

      Volume: 28 Issue: 6 Pages: 318-329

    • DOI

      10.1089/hgtb.2017.092

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] CRISPR/Cas9 Genome Editing Therapy for Hereditary Pulmonary Alveolar Proteinosis.2019

    • Author(s)
      Shima K, Suzuki T, Ma Y, Mayhew C, Sallese A, Carey BC, Arumugam P, Trapnell BC
    • Organizer
      American Thoracic Society 112th International Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Long-Term Follow-Up of a Patient with GM-CSF Antibody-Negative Pulmonary Alveolar Proteinosis Following Exposure to Dust After the Great East Japan Earthquake.2019

    • Author(s)
      Hisata S, Suzuki T, Yamauchi H, Ohkouchi S, Bando M, Hagiwara K
    • Organizer
      American Thoracic Society 112th International Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Gene Editing for Pulmonary Alveolar Proteinosis. Technology & Research Workshop. Gene Editing2018

    • Author(s)
      Suzuki T.
    • Organizer
      The 2018 International Rare Lung Disease Research Conference and LAMPOSIUM.
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Alveolar Macrophages and Lung Homeostasis. Symposium : Disease formation by macrophage dysfunction.2018

    • Author(s)
      Suzuki T.
    • Organizer
      The 91^<st> Annual Meeting of the Japanese Biochemical Society.
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Pulmonary Macrophage Transplantation (PMT) Therapy of Hereditary Pulmonary Alveolar Proteinosis (hPAP) Is Effective with Mature Macrophages without Progenitor Expansion Requirement.2017

    • Author(s)
      Suzuki T, Arumugam P, Sallese T, Shima K, Trapnell B. C
    • Organizer
      日本呼吸器学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Development and Validation of Csf2ra Gene-Deficient Mice as a Clinically Relevant Model of Children with Hereditary Pulmonary Alveolar Proteinosis.2017

    • Author(s)
      Suzuki T, Shima K, Arumugam P, Ma Y, Black D, Chalk C, Carey B, Trapnell B. C
    • Organizer
      American Thoracic Society 110th International Conference
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 遺伝性肺胞蛋白症に対する肺マクロファージ移植治療2017

    • Author(s)
      鈴木拓児、島賢治郎、Paritha Armugam、萩原弘一、Bruce Trapnell
    • Organizer
      第53回日本肺サーファクタント関連医学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Pulmonary Macrophage Transplantation Therapy in Csf2ra Gene-Deficient Mice, a Novel Clinically Relevant Model of Children with Hereditary Pulmonary Alveolar Proteinosis.2017

    • Author(s)
      Suzuki T, Shima K, Arumugam P, Trapnell B. C.
    • Organizer
      The 5th Annual Meeting of the International Cytokine and Interferon Society
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-24   Modified: 2022-06-09  

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