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The Role of Fibrinolytic and Coagulation Factors, a Subset of Angiocrine Factors in Cytokine Storm-Associated Diseases

Research Project

Project/Area Number 21K08404
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionJuntendo University

Principal Investigator

Hattori Koichi  順天堂大学, 大学院医学研究科, 特任先任准教授 (10360116)

Co-Investigator(Kenkyū-buntansha) 高橋 聡  東京大学, 医科学研究所, 特任教授 (60226834)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsアンジオクライン因子 / 血管内皮 / プロテアーゼ / バイオマーカー / COVID-19 / 遺伝子発現 / がん増殖 / 核酸製剤 / 血液内科学 / 免疫制御学 / 血栓止血学 / 血液免疫学 / 血液腫瘍学 / 血栓・止血学
Outline of Research at the Start

新型コロナウィルス感染症(COVID-19)の重症化に伴うサイトカインストームと血栓傾向は、予後に直結する病態として、その解明と対策は、世界的に臨床上喫緊の重要課題となっている。本研究では、血管内皮障害に基づくアンジオクライン因子によるサイトカインストーム発生制御機構の解明を主な目的とする。具体的には、COVID-19を含む炎症性疾患動物モデルと疾患患者検体を使用し、病勢に応じたアンジオクライン因子、炎症性サイトカインの血中濃度、病変臓器特異的血管内皮の性状変化、機能解析を進め、サイトカインストームの予見、早期診断、そして臓器特異的血管内皮関連分子を標的とした治療法開発の基盤形成を進めていく。

Outline of Final Research Achievements

In this study, the investigators elucidated the mechanisms of cytokine storm generation, cytokine storm syndrome (CSS) severity, and cancer growth by angiocrine factors triggered by vascular endothelial damage. Specifically, using murine models of CSS and cancer, we analyzed human COVID-19 samples, patient information, racial background, disease status, and clinical symptoms, as well as blood levels and activities of angiocrine factors and inflammatory cytokines, including blood coagulation and fibrinolytic factors. Angiocrine factors and inflammatory cytokines were driving tumor growth in murine models. The analysis of blood levels and activities of angiocrine factors, inflammatory cytokines, including fibrinolytic factors and metalloproteinases, endothelial properties, and functions were conducted, suggesting the possibility of early diagnosis of CSS using angiocrine factors as biomarkers. Furthermore, these molecular targets can also serve as novel treatment options for cancer.

Academic Significance and Societal Importance of the Research Achievements

サイトカインストーム症候群(CSS)は、自己免疫疾患や悪性腫瘍、そして最近まで世界中にパンデミックと経済危機をもたらしたCOVID-19に代表される新興・再興感染症の重症化病態と考えられており、極めて予後不良な状態を示唆する。その基礎疾患は、広範囲に渡るだけに、CSSの早期診断と治療法の開発は、人類の存亡を賭けた重要課題と言っても過言ではない。この課題に正面から向き合った本研究の社会的意義は極めて大きいものである。またその一方で、本研究は、各国のトップレベルの施設間連携による国際共同研究として進められ、研究成果はいずれも国際誌上で報告されており、その学術的意義も確固たるものと言えよう。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (34 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (6 results) Journal Article (14 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 14 results,  Open Access: 13 results) Presentation (11 results) (of which Int'l Joint Research: 1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Federal University of Bahia(ブラジル)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] An-Najah National University(パレスチナ(PLO))

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Cologn/University Hospital of Frankfurt/University Hospital of Augsburg(ドイツ)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Federal University of Bahia(ブラジル)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] An-Najah National University(パレスチナ(PLO))

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] An-Najah National University(パレスチナ(PLO))

    • Related Report
      2021 Research-status Report
  • [Journal Article] Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-192024

    • Author(s)
      Yatsenko Tetiana、Rios Ricardo、Nogueira Tatiane、Salama Yousef、Takahashi Satoshi、Tabe Yoko、Naito Toshio、Takahashi Kazuhisa、Hattori Koichi、Heissig Beate
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1299792-1299792

    • DOI

      10.3389/fimmu.2023.1299792

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The stem cell transcription factor ZFP296 transforms NIH3T3 cells and promotes anchorage-independent growth of cancer cells2023

    • Author(s)
      Mizoue Yumi、Ikeda Tomomi、Ikegami Takako、Riabets Oleksandra、Oishi Yoshie、Tobita Morikuni、Akutsu Hidenori、Hattori Koichi、Heissig Beate、Koide Hiroshi
    • Journal Title

      The International Journal of Developmental Biology

      Volume: 67 Issue: 4 Pages: 147-153

    • DOI

      10.1387/ijdb.230143hk

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity2023

    • Author(s)
      Yatsenko Tetiana、Skrypnyk Maksym、Troyanovska Olga、Tobita Morikuni、Osada Taro、Takahashi Satoshi、Hattori Koichi、Heissig Beate
    • Journal Title

      Cells

      Volume: 12 Issue: 3 Pages: 445-445

    • DOI

      10.3390/cells12030445

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Roles of extra cellular proteases in the pathogenesis and novel treatment of the cytokine storm syndrome2023

    • Author(s)
      服部浩一、島津浩、長田太郎、高橋聡、Heissig Beate
    • Journal Title

      Japanese Journal of Transplantation and Cellular Therapy

      Volume: 12 Issue: 4 Pages: 200-207

    • DOI

      10.7889/tct-23-016

    • ISSN
      2436-455X
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation2022

    • Author(s)
      Salama Yousef、Takahashi Satoshi、Tsuda Yuko、Okada Yoshio、Hattori Koichi、Heissig Beate
    • Journal Title

      Cancers

      Volume: 15 Issue: 1 Pages: 288-288

    • DOI

      10.3390/cancers15010288

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] COVID-19 severity and thrombo-inflammatory response linked to ethnicity2022

    • Author(s)
      Heissig B, Salama Y, Vehreschild JJ, Vehreschild MJGT, Mori H, Adachi E, Jakob C, Tabe Y, Ruethrich M, Borgmann S, Naito T, Wille K, Valenti S, Hower M, Hattori N, Rieg S, Nagaoka T, Jensen BE, Yotsuyanagi H, Hertenstein B, Ogawa H, Kominami E, Roemmele C, Takahashi S, Rupp J, Takahashi K, Hanses F, Hattori K
    • Journal Title

      Biomedicines

      Volume: 10 Issue: 10 Pages: 2549-2549

    • DOI

      10.3390/biomedicines10102549

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft-versus-host disease2022

    • Author(s)
      Heissig B, Salama Y, Tateno M, Takahashi S and Hattori K
    • Journal Title

      EJHaem

      Volume: 3 Issue: 3 Pages: 849-861

    • DOI

      10.1002/jha2.439

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] アンジオクラインシステムによるがん増殖制御機構2022

    • Author(s)
      服部浩一、島津浩、高橋聡、Heissig Beate
    • Journal Title

      日本血栓止血学会雑誌

      Volume: 33 Pages: 314-320

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] サイトカインストーム関連疾患に対する新規分子標的としての血液線維素溶解系因子群2022

    • Author(s)
      服部浩一、島津浩、高橋聡、Heissig Beate
    • Journal Title

      臨床血液

      Volume: 63 Pages: 403-409

    • Related Report
      2022 Research-status Report 2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft-versus-host disease2022

    • Author(s)
      Heissig B, Salama Y, Tateno M, Takahashi S and Hattori K
    • Journal Title

      eJHaem

      Volume: -

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 血液線維素溶解系と血管新生2022

    • Author(s)
      服部浩一、島津浩、高橋聡、Heissig Beate
    • Journal Title

      日本血栓止血学会雑誌

      Volume: -

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Aloysia Citrodora Essential Oil Inhibits Melanoma Cell Growth and Migration by Targeting HB-EGF-EGFR Signaling2021

    • Author(s)
      Salama Yousef、Jaradat Nidal、Hattori Koichi、Heissig Beate
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 15 Pages: 8151-8151

    • DOI

      10.3390/ijms22158151

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The multifaceted roles of EGFL7 in cancer and drug resistance.2021

    • Author(s)
      Heissig B*, Salama Y, Takahashi S, Okumura K, Hattori K
    • Journal Title

      Cancers

      Volume: 13(5) Issue: 5 Pages: 1014-1014

    • DOI

      10.3390/cancers13051014

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The multifacted role of plasminogen in Cancer.2021

    • Author(s)
      Heissig B*, Salama Y, Osada T, Okumura K, Hattori K.
    • Journal Title

      Intern. J of Molecular Sciences

      Volume: 22(5) Issue: 5 Pages: 2304-2304

    • DOI

      10.3390/ijms22052304

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 新しい核酸製剤NJA-312による造血幹細胞生着およびGVHDの制御機構の解明2024

    • Author(s)
      服部浩一, 高橋聡, 長田太郎, Heissig Beate
    • Organizer
      第23回日本再生医療学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] COVID-19 severity and thrombo-inflammatory response linked to ethnicity2023

    • Author(s)
      Hattori K, Takahashi S and Heissig B
    • Organizer
      第85回日本血液学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft-versus-host disease2023

    • Author(s)
      Hattori K, Takahashi S and Heissig B
    • Organizer
      第85回日本血液学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] COVID-19 後のプロテオリティック・ニッチにおける免疫系再構築機構の解明2023

    • Author(s)
      服部浩一, 高橋聡, 長田太郎, Heissig Beate
    • Organizer
      第22回日本再生医療学会総会
    • Related Report
      2022 Research-status Report
  • [Presentation] ES特異的転写因子Zfp296の細胞がん化への関与2022

    • Author(s)
      溝上優美,池田智美,池上 貴子, 服部浩一, Heissig Beate, 小出寛
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] Biomarkers and predictors of severe COVID-19: a comparative study of patients in Japan and Germany2022

    • Author(s)
      Hattori K, Takahashi S and Heissig B
    • Organizer
      第84回日本血液学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] サイトカインストーム症候群の病態解明と新規治療戦略2022

    • Author(s)
      服部浩一, 高橋聡, Heissig Beate
    • Organizer
      第44回日本造血・免疫細胞療法学会
    • Related Report
      2022 Research-status Report
  • [Presentation] The role of fibrinolytic factors, a subset of angiocrine factors in cytokine storm-associated diseases2022

    • Author(s)
      Hattori K, Heissig B
    • Organizer
      International Society for Stem Cell Research Jerusalem International Symposium "Stem Cells: From Genes to Organs"
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Fibrinolytic factors - novel molecular targets for cytokine storm-associated diseases2021

    • Author(s)
      Hattori K, Takahashi S and Heissig B
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Pathological control mechanism of multiple bone marrow species by angiocrine factor EGFL72021

    • Author(s)
      10.Hattori K, Yousef Salama, Satoshi Takahashi and Beate Heissig
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] アンジオクラインシステムによるサイトカインストーム制御機構の解明2021

    • Author(s)
      服部浩一, 高橋聡, 長田太郎, Heissig Beate
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2021 Research-status Report
  • [Remarks] 新型コロナウイルス感染症重症化の新しいバイオマーカーを同定

    • URL

      https://www.juntendo.ac.jp/news/17319.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 日独における新型コロナウイルス感染症の重症度と病態の比較

    • URL

      https://www.juntendo.ac.jp/news/00669.html

    • Related Report
      2022 Research-status Report
  • [Patent(Industrial Property Rights)] COVID-19の重症化を予測する血中バイオマーカー2023

    • Inventor(s)
      服部浩一、服部・ハイジッヒ・ベアテ、ヤツェンコ テチアナ
    • Industrial Property Rights Holder
      順天堂大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2023
    • Related Report
      2023 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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