A novel cytoprotective agent with thrombomodulin mutant

• Project/Area Number: 26461406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Fukushima Medical University (2016); Kochi University (2014-2015)
• Principal Investigator: Ikezoe Takayuki 福島県立医科大学, 医学部, 教授 (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): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: thrombomodulin / transplantation / SOS / トロンボモジュリン

Outline of Final Research Achievements

We previously reported that the 4th and 5th epidermal growth factor like domain of thrombomodulin (TME45) possesses cytoprotective as well as pro-angiogenic activities. The current study has found that these activities were preserved in the TME5. Further studies employed immunoprecipitation followed by proteomic analysis to identify the cell surface protein which interacts with TME5. We found that TME5 binds to chemokine receptor GPR15, leading to activation of intracellular pro-survival signaling in vascular endothelial cells.

Research Products

• [Int'l Joint Research] Xuzhou Medical University(China)
• [Journal Article] G-protein coupled receptor 15 mediates angiogenesis and cytoprotective function of thrombomodulin. (2017)
  • Author(s): Pan B, Wang X, Nishioka C, Honda G, Yokoyama A, Zeng L, Xu K, Ikezoe T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 692-701
  • DOI: 10.1038/s41598-017-00781-w
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Fifth Epidermal Growth Factor-like Region of Thrombomodulin Alleviates Murine Graft-versus-Host Disease in a G-Protein Coupled Receptor 15 Dependent Manner. (2017)
  • Author(s): Pan B, Wang X, Kojima S, Nishioka C, Yokoyama A, Honda G, Xu K, Ikezoe T.
  • Journal Title: Biol Blood Marrow Transplant Volume: 23 Issue: 5 Pages: 746-756
  • DOI: 10.1016/j.bbmt.2017.02.001
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15. (2017)
  • Author(s): Pan B, Wang X, Kojima S, Nishioka C, Yokoyama A, Honda G, Xu K, Ikezoe T.
  • Journal Title: Thromb Haemost. Volume: 117 Issue: 03 Pages: 570-579
  • DOI: 10.1160/th16-10-0762
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thrombomodulin blocks calcineurin inhibitor-induced vascular permeability via inhibition of Src/VE-cadherin axis. (2017)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Umezawa K, Yokoyama A.
  • Journal Title: Bone Marrow Transplant Volume: 52 Issue: 2 Pages: 245-251
  • DOI: 10.1038/bmt.2016.241
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model (2017)
  • Author(s): Takayuki Ikezoe, Jing Yang, Chie Nishioka, Bin Pan, Kailin Xu, Mutsuo Furihata, Keigo Nakamura, Hiroya Yurimoto, Yasuyoshi Sakai, Goichi Honda, and Akihito Yokoyama
  • Journal Title: Bone Marrow Transplant. Volume: 52 Issue: 1 Pages: 73-79
  • DOI: 10.1038/bmt.2016.195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship between HMGB1 and PAI-1 after allogeneic hematopoietic stem cell transplantation. (2016)
  • Author(s): Nomura S, Maeda Y, Ishii K, Katayama Y, Yagi H, Fujishima N, Ota S, Moriyama M, Ikezoe T, Miyazaki Y, Hayashi K, Fujita S, Satake A, Ito T, Kyo T, Tanimoto M.
  • Journal Title: J Blood Med. Volume: 7 Pages: 1-4
  • DOI: 10.2147/jbm.s93008
  • Peer Reviewed / Open Access
• [Journal Article] Disseminated intravascular coagulation in non-Hodgkin lymphoma. (2015)
  • Author(s): Chi S, Ikezoe T.
  • Journal Title: Int J Hematol Volume: 102 Issue: 4 Pages: 413-419
  • DOI: 10.1007/s12185-015-1854-5
  • Peer Reviewed
• [Journal Article] トロンボモジュリン (2015)
  • Author(s): 池添隆之
  • Journal Title: Thrombosis Medicine Volume: 5 Pages: 12-17
• [Journal Article] 造血細胞移植と肝中心静脈閉塞症 (2015)
  • Author(s): 池添隆之
  • Journal Title: Angiology Frontier Volume: 14 Pages: 33-39
• [Journal Article] 造血細胞移植とDIC-TAM/GVHDなどとの鑑別は？ (2015)
  • Author(s): 池添隆之
  • Journal Title: 血栓と循環 Volume: 23 Pages: 58-64
• [Journal Article] Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. (2015)
  • Author(s): Ikezoe T
  • Journal Title: J Intensive Care Volume: 3 Issue: 1 Pages: 1-8
  • DOI: 10.1186/s40560-014-0050-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen. (2015)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Yokoyama A.
  • Journal Title: Bone Marrow Transplant Volume: 50 Issue: 1 Pages: 113-120
  • DOI: 10.1038/bmt.2014.208
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin. (2014)
  • Author(s): Ikezoe T
  • Journal Title: Int J Hematol Volume: 100 Issue: 1 Pages: 27-37
  • DOI: 10.1007/s12185-013-1463-0
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] TME5はGPR15を介して血管内皮保護作用を発揮する (2016)
  • Author(s): 池添隆之、本田剛一
  • Organizer: 第３８回日本血栓止血学会学術集会
  • Place of Presentation: 奈良春日野国際フォーラム(奈良市)
  • Year and Date: 2016-06-08
• [Presentation] モノクロタリン誘発マウスSOSに対するトロンボモジュリン変異体の予防効果の検証 (2015)
  • Author(s): 池添隆之、西岡千恵、Jing Yang、降幡睦夫、本田剛一、横山彰仁
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府市総合市民会館（山梨県甲府市）
  • Year and Date: 2015-05-21
• [Presentation] The Fifth Region of Epidermal Growth Factor like-Domain of Thrombomodulin Is Essential to Produce Cytoprotection (2014)
  • Author(s): Takayuki Ikezoe
  • Organizer: 米国血液学会
  • Place of Presentation: サンフランシスコ (米国)
  • Year and Date: 2014-12-06 – 2014-12-10