Development of a novel treatment strategy to protect vascular endothelial cells with TM mutant

• Project/Area Number: 18H02844
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Ikezoe Takayuki 福島県立医科大学, 医学部, 教授 (80294833)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: トロンボモジュリン / 血管内皮細胞 / thrombomodulin / SOS / transplantation

Outline of Final Research Achievements

Thrombomodulin is a glycoprotein comprising several distinct structures and is mainly expressed on endothelial cell surfaces. TM negatively regulates the coagulation system and human recombinant TM consisting of an extracellular domain of TM is approved in Japan for treatment of patients with disseminated intravascular coagulation. We had recognized that rTM possesses vascular endothelial cytoprotective effects and initiated the experiments to explore the molecular mechanism by which rTM exerts cytoprotective effects and attempted to identify the minimal region of TM that produces cytoprotective function. We found that 19 amino acid structure within epidermal growth factor-like region of TM possesses angiogenic and cytoprotective function.

Academic Significance and Societal Importance of the Research Achievements

造血細胞移植は白血病をはじめ難治性血液がんに根治をもたらし得る画期的な治療法であるが、血管内皮細胞障害に起因する血栓性微小血管症や肝類洞閉塞症候群などによる非再発死亡が多く、その治療成績は未だ満足できるものではない。今回我々が見出した19アミノ酸を使用することで血管内皮細胞障害に起因する移植関連合併症を予防でき、移植成績の向上が期待できる。

Research Products

• [Int'l Joint Research] Xuzhou Medical University(中国)
• [Journal Article] Aurka deficiency in the intestinal epithelium promotes age-induced obesity via propionate-mediated AKT activation. (2021)
  • Author(s): Sun N, Meng F, Zhao J, Li X, Li R, Han J, Chen X, Cheng W, Yang X, Kou Y, Zheng K, Yang J, Ikezoe T.
  • Journal Title: Int J Biol Sci. Volume: 17 Issue: 5 Pages: 1302-14
  • DOI: 10.7150/ijbs.56477
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting HLA-F suppresses the proliferation of glioma cells via a reduction in hexokinase 2-dependent glycolysis. (2021)
  • Author(s): Chen X, Sun N, Li R, Sang X, Li X, Zhao J, Han J, Yang J, Ikezoe T.
  • Journal Title: Int J Biol Sci. Volume: 17 Issue: 5 Pages: 1263-76
  • DOI: 10.7150/ijbs.56357
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice. (2021)
  • Author(s): Minakawa K, Yokokawa T, Ueda K, Nakajima O, Misaka T, Kimishima Y, Wada K, Tomita Y, Miura S, Sato Y, Mimura K, Sugimoto K, Nakazato K, Nollet KE, Ogawa K, Ikezoe T, Hashimoto Y, Takeishi Y, Ikeda K.
  • Journal Title: J Hematol Oncol. Volume: 14 Issue: 1 Pages: 52-52
  • DOI: 10.1186/s13045-021-01064-8
  • Peer Reviewed / Open Access
• [Journal Article] Aurka loss in CD19+ B cells promotes megakaryocytopoiesis via IL-6/STAT3 signaling-mediated thrombopoietin production. (2021)
  • Author(s): Chen X, Wang C, Sun N, Pan S, Li R, Li X, Zhao J, Tong H, Tang Y, Han J, Qiao J, Qiu H, Wang H, Yang J, Ikezoe T.
  • Journal Title: Theranostics. Volume: 11 Issue: 10 Pages: 4655-71
  • DOI: 10.7150/thno.49007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chromosomal translocation t(11;14) and p53 deletion induced by the CRISPR/Cas9 system in normal B cell-derived iPS cells (2021)
  • Author(s): Yusuke Azami, Naohiro Tsuyama, Yu Abe, Misaki Sugai-Takahashi, Ken-Ichi Kudo, Akinobu Ota, Karnan Sivasundaram , Moe Muramatsu, Tomonari Shigemura, Megumi Sasatani, Yuko Hashimoto, Shigehira Saji, Kenji Kamiya, Ichiro Hanamura, Takayuki Ikezoe, Masafumi Onodera, Akira Sakai.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 5216-5216
  • DOI: 10.1038/s41598-021-84628-5
  • Peer Reviewed / Open Access
• [Journal Article] Hypofibrinogenemia is associated with a high degree of risk in infectious diseases: a post-hoc analysis of post-marketing surveillance of patients with disseminated intravascular coagulation treated with thrombomodulin alfa. (2021)
  • Author(s): Kawasugi K, Wada H, Honda G, Kawano N, Uchiyama T, Madoiwa S, Takezako N, Suzuki K, Seki Y, Ikezoe T, Iba T, Okamoto K.
  • Journal Title: Thromb J. Volume: 19 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s12959-021-00264-z
  • Peer Reviewed / Open Access
• [Journal Article] JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages. (2021)
  • Author(s): Li R, Sun N, Chen X, Li X, Zhao J, Cheng W, Hua H, Fukatsu M, Mori H, Takahashi H, Ohkawara H, Fukami M, Okamoto M, Hamazaki Y, Zheng K, Yang J, Ikezoe T.
  • Journal Title: Front Immunol. Volume: 11 Pages: 33628203-33628203
  • DOI: 10.3389/fimmu.2020.589048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review. (2021)
  • Author(s): Mori H, Ohkawara H, Togawa R, Rikimaru M, Shibata Y, Ikezoe T.
  • Journal Title: Int J Hematol. Volume: 113 Issue: 3 Pages: 320-29
  • DOI: 10.1007/s12185-021-03084-z
  • Peer Reviewed
• [Journal Article] Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib. (2021)
  • Author(s): Alkebsi L, Wang X, Ohkawara H, Fukatsu M, Mori H, Ikezoe T.
  • Journal Title: Int J Hematol. Volume: 113 Issue: 3 Pages: 441-455
  • DOI: 10.1007/s12185-020-03034-1
  • Peer Reviewed
• [Journal Article] Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies (2021)
  • Author(s): Ikezoe T
  • Journal Title: Int J Hematol. Volume: 113 Issue: 1 Pages: 34-44
  • DOI: 10.1007/s12185-020-02992-w
  • Peer Reviewed
• [Journal Article] Optimal timing of apheresis for the efficient mobilization of peripheral blood progenitor cells recruited by high-dose granulocyte colony-stimulating factor in healthy donors (2020)
  • Author(s): Kimura Satoshi、Ohkawara Hiroshi、Minakawa Keiji、Fukatsu Masahiko、Mori Hirotaka、Takahashi Hiroshi、Harada-Shirado Kayo、Ohara Yoshihiro、Takahashi Nobuhisa、Mochizuki Kazuhiro、Sano Hideki、Nollet Kenenth E、Ogawa Kazuei、Ohto Hitoshi、Kikuta Atsushi、Ikeda Kazuhiko、Ikezoe Takayuki
  • Journal Title: Transfusion and Apheresis Science Volume: - Issue: 3 Pages: 102737-102737
  • DOI: 10.1016/j.transci.2020.102737
  • Peer Reviewed
• [Journal Article] Analysis of the Association Between Resolution of Disseminated Intravascular Coagulation (DIC) and Treatment Outcomes in Post-Marketing Surveillance of Thrombomodulin Alpha for DIC With Infectious Disease and With Hematological Malignancy by Organ Failure (2020)
  • Author(s): Kawano N, Wada H, Uchiyama T, Kawasugi K, Madoiwa S, Takezako N, Suzuki K, Seki Y, Ikezoe T, Hattori T, Okamoto K.
  • Journal Title: Thromb J. Volume: - Issue: 1
  • DOI: 10.1186/s12959-020-0216-6
  • Peer Reviewed / Open Access
• [Journal Article] The Link Between interleukin-1β and Acute Myocardial Infarction in Chronic Myeloid Leukemia Patients Treated With Nilotinib: Cross-Sectional Study (2020)
  • Author(s): Mori H, Sukegawa M, Fukatsu M, Sano T, Takahashi H, Harada K, Kimura S, Ohkawara H, Nakamura K, Mita M, Saito T, Hamazaki Y, Ohta M, Ikezoe T.
  • Journal Title: Ann Hematol Volume: 99 Issue: 2 Pages: 359-361
  • DOI: 10.1007/s00277-019-03896-4
  • Peer Reviewed
• [Journal Article] Circulating Intranuclear Proteins May Play a Role in Development of Disseminated Intravascular Coagulation in Individuals With Acute Leukemia (2020)
  • Author(s): Harada-Shirado K, Wang X, Mori H, Fukatsu M, Takahashi H, Shichishima-Nakamura A, Kimura S, Ohkawara H, Yamada S, Ito T, Ikezoe T.
  • Journal Title: Int J Hematol. Volume: 111 Issue: 3 Pages: 378-387
  • DOI: 10.1007/s12185-019-02798-5
  • Peer Reviewed
• [Journal Article] Overview (2019)
  • Author(s): Ikezoe T
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 6 Pages: 646-646
  • DOI: 10.11406/rinketsu.60.646
  • NAID: 130007675223
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Management of transplant-associated thrombotic microangiopathy (2018)
  • Author(s): 池添 隆之
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 10 Pages: 2307-2314
  • DOI: 10.11406/rinketsu.59.2307
  • NAID: 130007496845
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2 (2018)
  • Author(s): Pan Bin、Yang Jing、Wang Xiangmin、Xu Kailin、Ikezoe Takayuki
  • Journal Title: Experimental Hematology Volume: 68 Pages: 80-88.e2
  • DOI: 10.1016/j.exphem.2018.09.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): Yakushijin Kimikazu、Ikezoe Takayuki、Ohwada Chikako、
  • Journal Title: Bone Marrow Transplantation Volume: 54 Issue: 5 Pages: 674-680
  • DOI: 10.1038/s41409-018-0304-4
  • Peer Reviewed
• [Journal Article] Cytoprotective and pro-angiogenic functions of thrombomodulin are preserved in the C loop of the fifth epidermal growth factor-like domain (2018)
  • Author(s): Wang Xiangmin、Pan Bin、Honda Goichi、Wang Xintao、Hashimoto Yuko、Ohkawara Hiroshi、Xu Kailin、Zeng Lingyu、Ikezoe Takayuki
  • Journal Title: Haematologica Volume: 103 Issue: 10 Pages: 1730-1740
  • DOI: 10.3324/haematol.2017.184481
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Defibrotide Stimulates Angiogenesis and Protects Endothelial Cells from Calcineurin Inhibitor-Induced Apoptosis via Upregulation of AKT/Bcl-xL. (2018)
  • Author(s): Wang X, Pan B, Hashimoto Y, Ohkawara H, Xu K, Zeng L, Ikezoe T.
  • Journal Title: Thromb Haemost Volume: 118 Pages: 161-173
• [Presentation] DIC離脱と転帰の相関に関するトロンボモジュリンアルファ製造販売後調査での感染症DICおよび造血器腫瘍DICを対象とした解析 (2020)
  • Author(s): 河野徳明, 和田英夫, 内山俊正, 川杉和夫, 窓岩清治, 竹迫直樹, 鈴木 圭, 関 義信, 池添隆之, 服部 剛, 岡本好司
  • Organizer: 第14回 日本血栓止血学会学術標準化委員会シンポジウム
• [Presentation] 造血器腫瘍に合併するDICへの核内蛋白の関与 (2020)
  • Author(s): 原田佳代, 王 新涛, 森 博隆, 深津真彦, 高橋裕志, 七島晶子, 木村 哲, 大河原浩, 山田晋吾, 伊藤隆史, 池添隆之
  • Organizer: 第14回 日本血栓止血学会学術標準化委員会シンポジウム
• [Presentation] 臨床に直結するDIC検査学 「急性白血病に合併するDICの発症機序について」 (2020)
  • Author(s): 池添隆之
  • Organizer: 第21回 日本検査血液学会学術集会
  • Invited
• [Presentation] 感染症型DICにおける低フィブリノゲン血症は予後不良である (2020)
  • Author(s): 和田英夫, 内山俊正, 川杉和夫, 窓岩清治, 竹迫直樹, 鈴木 圭, 関 義信, 池添隆之, 岡本好司, 射場敏明, 河野徳明
  • Organizer: 第42回 日本血栓止血学会学術集会
• [Presentation] 日本血栓止血学会DIC診断基準2017年版の有用性の評価と新規予後予測マーカーの検索 (2020)
  • Author(s): 池添隆之
  • Organizer: 第42回 日本血栓止血学会学術集会
  • Invited
• [Presentation] Stimulation of GPR15 on vascular endothelial cells mediates angiogenesis and cytoprotective function (2019)
  • Author(s): Masahiko Fukatsu, Xintao Wang , Lobna Alkebsi, Hiroshi Ohkawara, Goichi Honda, Takayuki Ikezoe.
  • Organizer: International Society on Thrombosis and Haemostasis (ISTH)2019
  • Int'l Joint Research
• [Presentation] Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia. (2019)
  • Author(s): Kayo Harada-Shirado, Xintao Wang , Masahiko Fukatsu, Hiroshi Takahashi , Akiko Shichishima-Nakamura , Satoshi Kimura, HiroshiOhkawara , Shingo Yamada, Takashi Ito, Takayuki Ikezoe.
  • Organizer: International Society on Thrombosis and Haemostasis (ISTH)2019
  • Int'l Joint Research
• [Presentation] 抗がん化学療法に発症する凝固異常症への核内蛋白の関与 (2019)
  • Author(s): 原田佳代, 王新涛, 森博隆, 深津真彦, 高橋裕志, 七島晶子, 木村哲, 大河原浩, 山田晋吾, 伊藤隆史, 池添隆之.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Recombinant human soluble thrombomodulin protects vascular endothelial cells from radiation-induced DNA damage (2018)
  • Author(s): Xiangmin Wang, Xintao Wang, Takakazu Kawase, Goichi Honda, Hiroshi Ohkawara, Takayuki Ikezoe
  • Organizer: 64th Annual ISTH SSC Meeting
  • Int'l Joint Research
• [Presentation] A critical role of growth arrest-specific gene 6-Mer axis in the pathogenesis of endothelial damage contributing to thrombotic microangiopathy associated with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): Miki Furukawa, Wang Xintao, Hiroshi Ohkawara, Masahiko Fukatsu, Lobna Alkebsi, Hideyoshi Noji, Kazuei Ogawa, Takayuki Ikezoe
  • Organizer: 60th American Society of Hematology (ASH) Annual Meeting and Exposition
  • Int'l Joint Research
• [Book] 造血細胞移植ガイドラインSOS/TA-TMA (2019)
  • Author(s): 池添隆之
  • Total Pages: 6
  • Publisher: 先端医学社
• [Book] 出血傾向を主訴に来院した高齢患者への対応 (2019)
  • Author(s): 池添隆之
  • Total Pages: 1
  • Publisher: 文光社
• [Book] 類洞閉塞症候群（SOS) (2019)
  • Author(s): 池添隆之
  • Total Pages: 11
  • Publisher: メディカルレビュー社
• [Book] DICと鑑別が必要な疾患 血栓性微小血管症（TMA) (2019)
  • Author(s): 池添隆之
  • Total Pages: 13
  • Publisher: メディカルレビュー社
• [Book] 播腫性血液内凝固（DIC) (2019)
  • Author(s): 池添隆之
  • Total Pages: 1
  • Publisher: 日本医事新報社
• [Book] 造血幹細胞移植後の免疫凝固異常 (2019)
  • Author(s): 大河原浩、池添隆之
  • Total Pages: 7
  • Publisher: 先端医学社
• [Book] 高齢者の凝固異常症 (2019)
  • Author(s): 原田佳代、池添隆之
  • Total Pages: 7
  • Publisher: 医薬ジャーナル社
• [Patent(Industrial Property Rights)] 新規ポリペプチド及びその用途 (2018)
  • Inventor(s): 池添隆之・本田剛一
  • Industrial Property Rights Holder: 福島県立医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas