Development of novel treatment strategy with TM to protect vascular endothelium

• Project/Area Number: 23591421
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kochi University
• Principal Investigator: IKEZOE TAKAYUKI 高知大学, 教育研究部医療学系, 講師 (80294833)
• Research Collaborator: NISHIOKA Chie 高知大学, 医学部, 研究員 ; YANG Jing 高知大学, 医学部, 外国人特別研究員
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: トロンボモジュリン / 血管内皮細胞

Research Abstract

Thrombomodulin (TM) is expressed on the cell surface of endothelial cells and regulates coagulation by inhibiting factor Va and VIIIa via activated protein C. This study found that TM increased levels of anti-apoptotic Mcl-1 in association with activation of extracellular signal-regulated kinase (ERK) and protected endothelial cells from endothelial cell damage caused by inflammatory cytokines and calcineurin inhibitors. Furthermore, we identified that cytoprotective function was localized in epidermal growth factor-like domain and independent from anti-coagulation.

Research Products

• [Journal Article] トロンボモジュリンの臨床応用 (2014)
  • Author(s): 池添隆之
  • Journal Title: 日本血栓止血学会誌 Volume: 25 Pages: 61-69
  • NAID: 130003393341
• [Journal Article] Pathogenesis of disseminate d intravascular coagulation in patien ts with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin (2013)
  • Author(s): Ikezoe T
  • Journal Title: Int J He matol Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Recombinant human solub le thrombomodulin is active against h emophagocytic lymphohistiocytosis ass ociated with acquired immunodeficienc y syndrome (2013)
  • Author(s): Chi S, Ikezoe T, Takeuchi A, Takaoka M, Yokoyama A
  • Journal Title: Int J Hematol Volume: 8(5) Pages: 615-9
  • Peer Reviewed
• [Journal Article] Effect o f recombinant human soluble thrombomo dulin on clinical outcomes of patient s with coagulopathy after hematopoiet ic stem cell transplantation (2013)
  • Author(s): Ikezoe T, Takeuchi A, Chi S, Takaoka M, Anabuki K, Kim T, Sakai M, Taniguc hi A, Togitani K, Yokoyama A
  • Journal Title: Eur J Ha ematol Volume: 91(5) Pages: 442-7
  • Peer Reviewed
• [Journal Article] Effect of recom binant human soluble thrombomodulin on clinical outcomes of patients with coagulopathy after hematopoietic stem cell transplantation (2013)
  • Author(s): Ikezoe T, Takeuchi A, ChiS, Anabuki K, Kim T, Sakai M, Taniguchi A, Togitani K, Yokoyama A
  • Journal Title: Eur J Haematol Volume: 91 Issue: 5 Pages: 442-447
  • DOI: 10.1111/ejh.12188
  • Peer Reviewed
• [Journal Article] Recombinant human soluble thrombomodulin is active against hemophagocytic lymphohistiocytosis associated with acquired immunodeficiency syndrome. (2013)
  • Author(s): Chi S, Ikezoe T, Takeuchi A, Takaoka M, Yokoyama A.
  • Journal Title: Int J Hematol. Volume: 98 Issue: 5 Pages: 615-619
  • DOI: 10.1007/s12185-013-1450-5
  • Peer Reviewed
• [Journal Article] 造血器腫瘍による類洞閉塞症候群の発症機構と治療のポイント (2012)
  • Author(s): 池添隆之
  • Journal Title: Throm bosis Medicine Volume: 2 Pages: 79-83
• [Journal Article] Recombinant human soluble thrombomodu lin safely and effectively rescues ac ute promyelocytic leukemia patients f rom disseminated intravascular coagul ation (2012)
  • Author(s): Ikezoe T, Takeuchi A, Isaka M, Arakaw a Y, Iwabu N, Kin T, Anabuki K, Sakai M, Taniguchi A, Togitani K, Yokoyama A
  • Journal Title: Leuk Res Volume: 36(11) Pages: 1398-402
  • Peer Reviewed
• [Journal Article] Thrombomodulin enhance es the antifibrinolytic and antileuke mic e ffects of all-trans retinoic a cid in acute promyelocytic leukemia cells (2012)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Isaka M Iwabu N, Sakai M, Taniguchi A, Honda G, Yokoyama A
  • Journal Title: Exp Hematol Volume: 40(6) Pages: 457-65
  • Peer Reviewed
• [Journal Article] Thrombomodulin-induced dif ferentiation of acute myelomonocytic l eukemia cells via JNK signaling (2012)
  • Author(s): Yang J, Ikezoe T, Nishioka C, Honda G, Yokoyama A
  • Journal Title: Leuk Res Volume: 36(5) Pages: 625-33
  • Peer Reviewed
• [Journal Article] Thrombomodulin protects endothelial cells from a calc ineurin inhibitor-induced cytotoxicity by upregulation of extracellular signa l-regulated kinase/myeloid leukemia ce ll-1 signaling (2012)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Honda G, Furihata M, Yokoyama A
  • Journal Title: Arterioscler Thromb Va sc Biol Volume: 32(9) Pages: 2259-70
  • Peer Reviewed
• [Journal Article] Thrombomodulin Protects Endothelial Cells From a Calcineurin Inhibitor-Induced Cytotoxicity by Upregulation of Extracellular Signal-Regulated Kinase/Myeloid Leukemia Cell-1 Signaling. (2012)
  • Author(s): Ikezoe T
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Issue: 9 Pages: 2259-2270
  • DOI: 10.1161/atvbaha.112.251157
  • Peer Reviewed
• [Journal Article] Thrombomodulin-induced differentiation of acute myelomonocytic leukemia cells via JNK signaling. (2012)
  • Author(s): Yang J, Ikezoe T, Nishioka C, Honda G, Yokoyama A.
  • Journal Title: Leukemia Research Volume: 36 Issue: 5 Pages: 625-33
  • DOI: 10.1016/j.leukres.2012.01.019
  • Peer Reviewed
• [Journal Article] Thrombomodulin enhances the antifibrinolytic and antileukemic effects of all-trans retinoic acid in acute promyelocytic leukemia cells. (2012)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Isaka M, Iwabu N, Sakai M, Taniguchi A, Honda G, Yokoyama A.
  • Journal Title: Exp Hematol. Volume: 40 Issue: 6 Pages: 457-65
  • DOI: 10.1016/j.exphem.2012.01.016
  • Peer Reviewed
• [Journal Article] Thrombomodulin-induced differentiation of acute myelomonocytic leukemia cells via JNK signaling (2011)
  • Author(s): Yang J, Ikezoe T, Nishioka C, Honda G, Yokoyama A
  • Journal Title: Leukemia Research Volume: 36 Pages: 625-633
  • Peer Reviewed
• [Presentation] Molecular mechanisms by which calcine urin inhibitors increase vascular perm eability (2013)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Yokoyama A
  • Organizer: 第35回日本血栓止血学会
  • Place of Presentation: 山形国際ホテル,山形
• [Presentation] トロンボモジュリンの血管内皮細胞保護作用の検証 (2012)
  • Author(s): 池添隆之
  • Organizer: 第12回DIC研究会
  • Place of Presentation: 東京千代田区丸の内三菱コンファレンススクエアM+東京
  • Year and Date: 2012-03-03
  • Invited
• [Presentation] Thrombomodulin protects endothielial cells by upregulation of ERK/Mcl-1 si gnaling (2012)
  • Author(s): Ikezoe T
  • Organizer: 第34回日本血栓止血学会
  • Place of Presentation: ハイアットリージェンシー東京,東京
• [Presentation] Thrombomodulin protects endothelial cells by upregulation of ERK/Mcl-1 signaling. (2012)
  • Author(s): 池添隆之
  • Organizer: 第34回日本血栓止血学会
  • Place of Presentation: ハイアットリージェンシー東京（東京）
• [Presentation] トロンボモジュリンの血管内皮細胞保護作用の検証 (2012)
  • Author(s): 池添隆之
  • Organizer: 第12回日本ＤＩＣ研究会(招待講演)
  • Place of Presentation: 東京千代田区丸の内三菱ビルコンファレンススクエアM+
• [Book] 血液フロンティア (2011)
  • Author(s): 池添隆之
  • Total Pages: 10
  • Publisher: 医薬ジャーナル社
• [Patent(Industrial Property Rights)] 新規なポリペプチド及びその用途 (2013)
  • Inventor(s): 池 添隆之、横山彰仁、本田剛一
  • Industrial Property Rights Holder: 国立大学法人高知大学、旭化成ファーマ株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-199627
  • Filing Date: 2013-09-26
  • Overseas
• [Patent(Industrial Property Rights)] 新規なポリペプチド及びその用途 (2013)
  • Inventor(s): 池添隆之
  • Industrial Property Rights Holder: 池添隆之
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-09-24
• [Patent(Industrial Property Rights)] 造血細胞移植に伴う生着症候群の予防 及び/又は治療剤 (2011)
  • Inventor(s): 池添隆之、横山彰仁
  • Industrial Property Rights Holder: 国立大学法人高知大学、旭化成ファーマ株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2011-131768
  • Filing Date: 2011-06-14
  • Overseas
• [Patent(Industrial Property Rights)] Method for prophylactic and/or the rapeutic treatment of pain associ ated with hematopoietic cell tran splantation (2011)
  • Inventor(s): 池添隆之、横山彰仁
  • Industrial Property Rights Holder: 国立大大学法人高知大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2011-08-26
  • Overseas