Development of new therapy of inflammatory diseases in parenchymal organs by fibrinolytic pathway

• Project/Area Number: 15K21373
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery; Gastroenterology
• Research Institution: Juntendo University
• Principal Investigator: TASHIRO Yoshihiko 順天堂大学, 医学部, 非常勤助教 (20636245)
• Co-Investigator(Renkei-kenkyūsha): HATTORI Koichi 東京大学, 大学院・医科学研究所, 特任准教授 (10360116)
• Research Collaborator: SAKAMOTO Kazuhiro 順天堂大学, 医学部, 教授 (60205763)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Plasmin / 炎症性疾患 / MMP-9 / 線維素溶解系 / plasmin / MMP / TNF-α / 骨髄由来細胞 / 急性肝炎 / 線維素溶解系因子 / プラスミン阻害剤 / マクロファージ / 単球 / プラスミン / 肝炎 / 血球貪食症候群

Outline of Final Research Achievements

We prepared a severe acute hepatitis mouse model, elucidated the role of fibrinolytic system, and developed new therapy.
In the pathogenesis of acute hepatitis, the activity of coagulation and fibrinolytic factors and the activation of various MMPs (matrix metalloproteinase) were revealed. Since pathological findings of acute hepatitis were improved in these gene - deficient mice, it was revealed that MMP activity accompanying enhancement of fibrinolytic system controls acute hepatitis pathology. By administering a novel drug YO-2 that inhibits the fibrinolytic factor plasmin, inflammatory cytokines are suppressed in acute hepatitis model mice, acute hepatitis can be controlled, and future clinical applications are expected .

Research Products

• [Journal Article] Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice. (2017)
  • Author(s): Honjo K, Munakata S, Tashiro Y, Salama Y, Shimazu H, Eiamboonsert S, Dhahri D, Ichimura A, Dan T, Miyata T, Takeda K, Sakamoto K, Hattori K, Heissig B.
  • Journal Title: FASEB Journal Volume: - Issue: 6 Pages: 2625-2637
  • DOI: 10.1096/fj.201600871rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome (2017)
  • Author(s): 1.Shimazu H, Munakata S, Tashiro Y, Salama Y, Eiamboonser S, Ohta Y, Onoda H, Tsuda Y, Okada Y, Nakauchi H, Heissig B and Hattori K
  • Journal Title: Blood Volume: 印刷中 Issue: 1 Pages: 59-72
  • DOI: 10.1182/blood-2016-09-738096
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The fibrinolytic pathway expands the murine bone marrow mesenchymal stem/stromal cells through a crosstalk with endothelial cells (2016)
  • Author(s): 3.Dhahri D, Sato-Kusubata K, Ohki-Koizumi M, Nishida C, Tashiro Y, Munakata S, Shimazu H, Salama Y, Eiamboonser S, Nakauchi H, Hattori K and Heissig B
  • Journal Title: Blood Volume: 128 Issue: 8 Pages: 1063-1075
  • DOI: 10.1182/blood-2015-10-673103
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cancer therapy targeting the fibrinolytic system (2016)
  • Author(s): Heissig B, Eiamboonsert S, Salama Y, Shimazu H, Dhahri D, Munakata S Tashiro Y and Hattori K
  • Journal Title: Advanced Drug Delivery Rev Volume: 印刷中 Pages: 172-179
  • DOI: 10.1016/j.addr.2015.11.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intrathoracic Hernia after Total Gastrectomy (2016)
  • Author(s): Tashiro Y. Murakami M. Otsuka K. Saito K. Saito A. Motegi K. Date H. Yamashita T. Ariyoshi T. Goto S. Yamazaki K. Fujimori A. Watanabe M. Aoki T.
  • Journal Title: Case Report in Gastroenterolgy Volume: 1 Issue: 1 Pages: 1-6
  • DOI: 10.1159/000443268
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical pathway to discharge 3 days after colorectal endscopic submucosal dissection. (2015)
  • Author(s): Tomiki Y, Kawai M, Takehara K, Tashiro Y, Munakata S, Kazumasa K, Ishiyama S, Sugimoto K, Kamiyama H, Takahashi M, Sakamoto K
  • Journal Title: Digestive Endoscopy Volume: 27 Issue: 6 Pages: 679-686
  • DOI: 10.1111/den.12468
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Single-Incision Laparoscopic Colostomy or Ileostomy for Unresectable Colorectal Cancer (2015)
  • Author(s): Kawai M, Sakamoto K, Tomiki Y,Okuzawa A, Goto M, Kojima Y, Takahashi M, Komiyama H, Sugimoto K, Ishiyama S, Niwa K, Tashiro Y, Munakata S, Takehara K
  • Journal Title: Juntendo Medical Journal Volume: 61 Issue: 2 Pages: 153-157
  • DOI: 10.14789/jmj.61.153
  • NAID: 130005093621
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 血球貪食症候群の病態における線溶系の機能解析 (2017)
  • Author(s): 島津浩、田代良彦
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 血球貪食症候群における線溶系の機能解析 (2017)
  • Author(s): 島津浩、田代良彦
  • Organizer: 第13回血液学若手研究者勉強会
• [Presentation] Roles of plasmin for the progression of HPS/MAS in mice (2016)
  • Author(s): 島津浩、田代良彦、Beate Heissig、服部浩一
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] Roles of fibrinolytic factors for the progression of HPS/MAS (2015)
  • Author(s): 島津浩、宗像慎也、田代良彦、中内啓光、Beat Heissig、服部浩一
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 石川県
  • Year and Date: 2015-10-16