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Development of a novel treatment for eosinophilic sinusitis by controlling the fibrinolytic system.

Research Project

Project/Area Number 20K09686
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56050:Otorhinolaryngology-related
Research InstitutionUniversity of Fukui

Principal Investigator

Takabayashi Tetsuji  福井大学, 学術研究院医学系部門(附属病院部), 講師 (70397272)

Co-Investigator(Kenkyū-buntansha) 加藤 幸宣  福井大学, 学術研究院医学系部門(附属病院部), 助教 (00748981)
吉田 加奈子  福井大学, 学術研究院医学系部門(附属病院部), 特命助教 (00773706)
坂下 雅文  福井大学, 学術研究院医学系部門(附属病院部), 講師 (40555455)
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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords好酸球性副鼻腔炎 / フィブリン / 組織型プラスミノーゲンアクチベーター / 好酸球 / M2マクロファージ / 鼻茸 / 凝固系 / 線溶系 / 組織型プラスミノーゲンアクチベータ / 慢性副鼻腔炎 / tPA / フィブリン網 / 肥満細胞
Outline of Research at the Start

好酸球性副鼻腔炎における治療の成否は難治性で易再発性の鼻茸をいかにコントロールするかにかかっている。しかし現時点で決定的な治療法はない。申請者はこれまでに鼻・副鼻腔粘膜における過剰なフィブリン網の沈着が浮腫を遷延させ、鼻茸形成に関与することを明らかにした。本研究では、組織内で過剰に形成されたフィブリン網の合成、および分解に重要な、凝固・線溶系の制御機構、またこれらに対する肥満細胞の関与、そして腸内細菌が鼻粘膜における線溶系に与える影響について、摘出標本、培養細胞、モデルマウスを用いて検討し、新規治療法の開発につなげる。

Outline of Final Research Achievements

In eosinophilic sinusitis, it is of great importance to understand the mechanism of nasal mushroom formation, and our previous studies have shown that excessive fibrin network formation in the nasal sinus mucosa is responsible for the prolonged oedema. In the present study, we have demonstrated the involvement of M2 macrophages infiltrating the nasal sinus mucosa in the enhancement of the coagulation system. Furthermore, Nasal NO was significantly decreased in eosinophilic sinusitis and could be a biomarker for the condition, or could provide more useful information than endoscopic findings when deciding whether to continue or reduce the use of biologics.

Academic Significance and Societal Importance of the Research Achievements

好酸球性副鼻腔炎は難治性の疾患で指定難病にも登録されている。鼻副鼻腔粘膜の浮腫の遷延によって形成される鼻茸は鼻腔に特徴的な病変で同じ気道の2型炎症性疾患である気管支喘息やアトピー性皮膚炎患者においてこのような病変の局所での形成は認められない。好酸球性副鼻腔炎おいて鼻茸の形成メカニズムを解明することは非常に重要であるが、本結果は凝固線溶系の不均衡を解除し新規治療法の開発に有用であると考えられた。

Report

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

    (28 results)

All 2023 2022 2021 2020

All Journal Article (12 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 12 results,  Open Access: 8 results) Presentation (15 results) (of which Int'l Joint Research: 5 results,  Invited: 11 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Retinoic acid promotes fibrinolysis and may regulate polyp formation.2022

    • Author(s)
      Sakashita M, Haruna S, et al.
    • Journal Title

      J Allergy Clin Immunol.

      Volume: 150 Issue: 5 Pages: 1114-1124

    • DOI

      10.1016/j.jaci.2022.05.021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Elevated Serum Leptin Levels in Patients With Eosinophilic Chronic Rhinosinusitis2022

    • Author(s)
      Imoto Yoshimasa、Ueki Shigeharu、Kato Yukinori、Yoshida Kanako、Morikawa Taiyo、Kimura Yukihiro、Kidoguchi Masanori、Tsutsumiuchi Toshiki、Koyama Keisuke、Adachi Naoto、Ito Yumi、Ogi Kazuhiro、Sakashita Masafumi、Yamada Takechiyo、Schleimer Robert P.、Takabayashi Tetsuji、Fujieda Shigeharu
    • Journal Title

      Frontiers in Pharmacology

      Volume: 12 Pages: 793607-793607

    • DOI

      10.3389/fphar.2021.793607

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Regulation of the Expression of SARS-CoV-2 Receptor Angiotensin-Converting Enzyme 2 in Nasal Mucosa2021

    • Author(s)
      Takabayashi Tetsuji、Yoshida Kanako、Imoto Yoshimasa、Schleimer Robert P.、Fujieda Shigeharu
    • Journal Title

      American Journal of Rhinology & Allergy

      Volume: 36 Issue: 1 Pages: 115-122

    • DOI

      10.1177/19458924211027798

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Phase II, Multicenter, Randomized, Placebo-Controlled Study of Benralizumab, a Humanized Anti-IL-5R Alpha Monoclonal Antibody, in Patients With Eosinophilic Chronic Rhinosinusitis.2021

    • Author(s)
      Takabayashi T, Asaka D, Okamoto Y, et al.
    • Journal Title

      Am J Rhinol Allergy.

      Volume: 35(6) Issue: 6 Pages: 861-870

    • DOI

      10.1177/19458924211009429

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ORMDL3 overexpression facilitates FcεRI‐mediated transcription of proinflammatory cytokines and thapsigargin‐mediated PERK phosphorylation in RBL‐2H3 cells2021

    • Author(s)
      Ogi Kazuhiro、Takabayashi Tetsuji、Tomita Kaori、Sakashita Masafumi、Morikawa Taiyo、Ninomiya Takahiro、Okamoto Masayuki、Narita Norihiko、Fujieda Shigeharu
    • Journal Title

      Immunity, Inflammation and Disease

      Volume: 9 Issue: 4 Pages: 1394-1405

    • DOI

      10.1002/iid3.489

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Baicalin suppresses type 2 immunity through breaking off the interplay between mast cell and airway epithelial cell2021

    • Author(s)
      Yoshida K, Takabayashi T, Kaneko A, Takiyama M, Sakashita M, Imoto Y, Kato Y, Narita N, Fujieda S.
    • Journal Title

      Journal of Ethnopharmacology

      Volume: 1;267 Pages: 113492-113492

    • DOI

      10.1016/j.jep.2020.113492

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparison of sensitization and prevalence of Japanese cedar pollen and mite-induced perennial allergic rhinitis between 2006 and 2016 in hospital workers in Japan2021

    • Author(s)
      Sakashita M, Tsutsumiuchi T, Kubo S, Tokunaga T, Takabayashi T, Imoto Y, Kato Y, Yoshida K, Kimura Y, Kato Y, Kanno M, Ogi K, Okamoto M, Narita N, Fujieda S.
    • Journal Title

      Allergology International

      Volume: 70 Issue: 1 Pages: 89-95

    • DOI

      10.1016/j.alit.2020.07.004

    • NAID

      130007966780

    • ISSN
      1323-8930, 1440-1592
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased Thrombin-Activatable Fibrinolysis Inhibitor in Response to Sublingual Immunotherapy for Allergic Rhinitis2021

    • Author(s)
      Yoshida K, Takabayashi T, Imoto Y, Sakashita M, Kato Y, Narita N, Fujieda S.
    • Journal Title

      Laryngoscope

      Volume: 12 Issue: 11 Pages: 2413-2420

    • DOI

      10.1002/lary.29563

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epidemiological study of oral allergy syndrome in birch pollen dispersal-free regions2020

    • Author(s)
      Osawa Y, Ito Y, Fujieda S, et al.
    • Journal Title

      Allergology International

      Volume: 69 Issue: 2 Pages: 246-252

    • DOI

      10.1016/j.alit.2019.09.008

    • NAID

      130007832960

    • ISSN
      1323-8930, 1440-1592
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis2020

    • Author(s)
      Oka A, Ninomiya T, Fujiwara T, Takao S, Sato Y, Gion Y, Minoura A, Haruna SI, Yoshida N, Sakuma Y, Izuhara K, Ono J, Taniguchi M, Haruna T, Higaki T, Kariya S, Koyama T, Takabayashi T, Imoto Y, Sakashita M, Kidoguchi M, Nishizaki K, Fujieda S, Okano M.
    • Journal Title

      Allergology International

      Volume: 69 Issue: 3 Pages: 417-423

    • DOI

      10.1016/j.alit.2019.12.004

    • NAID

      130007877682

    • ISSN
      1323-8930, 1440-1592
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced 15-Lipoxygenase 1 Production is Related to Periostin Expression and Eosinophil Recruitment in Eosinophilic Chronic Rhinosinusitis2020

    • Author(s)
      Imoto Y, Takabayashi T, Sakashita M, Kato Y, Yoshida K, Kidoguchi M, Koyama K, Adachi N, Kimura Y, Ogi K, Ito Y, Kanno M, Okamoto M, Narita N, Fujieda S.
    • Journal Title

      Biomolecules

      Volume: 18;10(11) Issue: 11 Pages: 1568-1568

    • DOI

      10.3390/biom10111568

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between the NOS2 pentanucleotide repeat polymorphism and risk of postoperative recurrence of chronic rhinosinusitis with nasal polyps in a Japanese population.2020

    • Author(s)
      Kidoguchi M, Yoshida K, Noguchi E, Nakamura T, Morii W, Haruna T, Okano M, Yamashita Y, Haruna S, Hasegawa M, Yoshida N, Ninomiya T, Imoto Y, Sakashita M, Takabayashi T, Fujieda S.
    • Journal Title

      Allergology International

      Volume: 69(4) Issue: 4 Pages: 619-621

    • DOI

      10.1016/j.alit.2020.04.005

    • NAID

      130007926244

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 酸化ストレスが好酸球性副鼻腔炎の病態に与える影響についての検討2023

    • Author(s)
      高林哲司
    • Organizer
      第3回耳鼻咽喉科免疫アレルギー感染症学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 病態から考えた好酸球性副鼻腔炎の治療選択2023

    • Author(s)
      高林哲司
    • Organizer
      第43回 日本耳鼻咽喉科頭頸部外科学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Coagulation and Nasal Polyp Formation2022

    • Author(s)
      Takabayashi Tetsuji
    • Organizer
      AAAAI
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Biologic drugs for the treatment of chronic rhinosinusitis with nasal polyps2022

    • Author(s)
      Takabayashi Tetsuji
    • Organizer
      18th Japan-Korea Joint Meeting of Otorhinolaryngology-Head and Neck Surgery
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 好酸球性副鼻腔炎のバイオマーカーと治療の可能性に関する検討2022

    • Author(s)
      高林哲司
    • Organizer
      第71回日本アレルギー学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Coagulation and Nasal Polyp Formation2022

    • Author(s)
      Tetsuji Takabayashi
    • Organizer
      2022 AAAAI Annual Meeting
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Biologic drugs for the treatment of chronic rhinosinusitis with nasal polyps2022

    • Author(s)
      Tetsuji Takabayashi
    • Organizer
      18th Japan-Korea Joint Meeting of Otorhinolaryngology Head and Neck Surgery
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Type2炎症をターゲットにした好酸球性副鼻腔炎治療2021

    • Author(s)
      高林哲司
    • Organizer
      第60回日本鼻科学会総会・学術講演会、ならびに20th Asian Research Symposium in Rhinology
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] IL-4/13を標的にした好酸球性副鼻腔炎治療の可能性2021

    • Author(s)
      高林哲司
    • Organizer
      第70回日本アレルギー学会学術大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 鼻茸を伴う慢性鼻副鼻腔炎(CRSwNP)における鼻茸スコアおよびType2炎症biomarkerに対するdupilumabの効果2021

    • Author(s)
      高林哲司
    • Organizer
      第70回日本アレルギー学会学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 増加するアレルギー性鼻炎とその対策2021

    • Author(s)
      高林哲司
    • Organizer
      富山県呉西地区耳鼻咽喉科症例研究会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 慢性気道炎症性疾患制御に向けた 治療アプローチ2020

    • Author(s)
      高林哲司
    • Organizer
      日本耳鼻咽喉科学会秋季大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] デュピルマブによる鼻茸を伴う慢性副鼻腔炎患者の血液、尿、および鼻汁におけるType2炎症バイオマーカーの抑制:SINUS-52 第3相臨床試験2020

    • Author(s)
      高林哲司
    • Organizer
      第59回日本耳鼻咽喉科学会総会・学術講演会
    • Related Report
      2020 Research-status Report
  • [Presentation] 鼻茸を伴う慢性副鼻腔炎の発症と 病態におけるType2炎症の役割2020

    • Author(s)
      高林哲司
    • Organizer
      第59回日本耳鼻咽喉科学会総会・学術講演会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 好酸球性副鼻腔炎の 鼻ポリープ形成メカニズムとその制御の可能性2020

    • Author(s)
      高林哲司
    • Organizer
      Type2炎症性疾患治療を考える会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Patent(Industrial Property Rights)] 気道上皮細胞のAngiotensin-converting enzyme 2 (ACE2)制御による 新型コロナウィルス; SARS-CoV-2 (COVID-19)感染対策2020

    • Inventor(s)
      高林哲司、吉田加奈子、意元義政、藤枝重治
    • Industrial Property Rights Holder
      高林哲司、吉田加奈子、意元義政、藤枝重治
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-146169
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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

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