The effect of thrombomodulin on acute radiation injury

• Project/Area Number: 20K21582
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Fukushima Medical University
• Principal Investigator: Takayuki Ikezoe 福島県立医科大学, 医学部, 教授 (80294833)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: トロンボモジュリン / 急性放射線症候群 / 放射線障害

Outline of Research at the Start

in vitro実験：マウスの骨髄から造血幹細胞を、そして肝臓の血管からは血管内皮幹細胞を採取してトロンボモジュリン（TM)あるいはコントロール溶媒の存在下で培養して、TMがこれらの幹細胞の増殖を増強するのか検証する。in vivo実験：C57BLマウスに放射線照射を行い骨髄造血障害と血管内皮細胞障害を誘導する。このマウスに緑色に発色するマウス血管内皮幹細胞と赤色に光る造血幹細胞を移植した後にTMあるいはコントロール溶媒を投与する。TMにより血管や骨髄造血の回復が促進することを確認する。

Outline of Final Research Achievements

Thrombomodulin (TM), a multi-domain membrane protein expressed on vascular endothelial cells, binds to thrombin and converts protein C to activated protein C (APC), exerting anticoagulant effects. In experiments using human umbilical vein vascular endothelial cells, TM inhibited phosphorylation of γH2AX, a marker of radiation-induced DNA damage. We generated a TM mutant, TM G412D, which does not bind thrombin and is unable to produce APC, and TM G412G enhanced proliferation and angiogenesis of human umbilical vein vascular endothelial cells; TM G412D may be a promising therapeutic agent for acute radiation syndrome.

Academic Significance and Societal Importance of the Research Achievements

東京電力福島第一原子力発電所では今後廃炉作業が進められる。起きてはならないことではあるが、その発生リスクがゼロではない被ばく事故に備えた対策の確立が望まれる。特に1グレイ以上の線量を被ばくした際に生じる骨髄不全や消化管障害などからなる急性放射線症候群に対する治療法の確立は急務である。本研究により、放射線によるDNA損傷をTMが緩和する可能性や、放射線傷害の結果生じるフリーラジカルによる肺障害をTMが緩和する可能性が示された。TMは抗凝固薬であるため、被ばく患者に使用すると出血を助長することが危惧される。我々が合成したTM G412Dは凝固系に作用しないため安全に使用可能である。

Research Products

• [Int'l Joint Research] Xuzhou Medical University(中国)
• [Journal Article] Sepsis-Associated DIC with Decreased Levels of Antithrombin and Fibrinogen is the Target for Combination Therapy with Thrombomodulin Alfa and Antithrombin. (2023)
  • Author(s): Wada H, Kawasugi K, Honda G, Kawano N, Uchiyama T, Madoiwa S, Takezako N, Suzuki K, Seki Y, Ikezoe T, Iba T, Okamoto K.
  • Journal Title: TH Open Volume: 7 Issue: 01 Pages: e65-e75
  • DOI: 10.1055/a-2009-9073
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of a quantitative PCR based method for chimerism analysis of Japanese donor/ recipient pairs (2022)
  • Author(s): Keiji Minakawa, Satoshi Ono, Mao Watanabe, Yuka Sato, Saki Suzuki, Shou Odawara, Kinuyo Kawabata, Koki Ueda, Kenneth E. Nollet, Hideki Sano, Takayuki Ikezoe, Atsushi Kikuta& Kazuhiko Ikeda
  • Journal Title: Scientifc Reports Volume: 12 Issue: 1 Pages: 21328-21328
  • DOI: 10.1038/s41598-022-25878-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS (2022)
  • Author(s): Fukatsu Masahiko、Ohkawara Hiroshi、Wang Xintao、Alkebsi Lobna、Furukawa Miki、Mori Hirotaka、Fukami Miwa、Fukami Shin-ichi、Sano Takahiro、Takahashi Hiroshi、Harada-Shirado Kayo、Kimura Satoshi、Sugimoto Koichi、Ogawa Kazuei、Ikezoe Takayuki
  • Journal Title: Science Signaling Volume: 15 Issue: 724
  • DOI: 10.1126/scisignal.abd2533
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. (2022)
  • Author(s): Li R, Li X, Zhao J, Meng F, Yao C, Bao E, Sun N, Chen X, Cheng W, Hua H, Li X, Wang B, Wang H, Pan X, You H, Yang J, Ikezoe T.
  • Journal Title: Theranostics. Volume: 12 Issue: 2 Pages: 976-999
  • DOI: 10.7150/thno.63751
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells. (2020)
  • Author(s): Han J, Jiang Z, Wang C, Chen X, Li R, Sun N, Liu X, Wang H, Hong L, Zheng K, Yang J, Ikezoe T.
  • Journal Title: Mol Cancer Res. Volume: 10 Issue: 10 Pages: 1589-1602
  • DOI: 10.1158/1541-7786.mcr-19-1226
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using 211At-CXCR4 monoclonal antibody. (2020)
  • Author(s): Oriuchi N
  • Journal Title: Sci. Rep. Volume: 10 Issue: 1 Pages: 6810-6810
  • DOI: 10.1038/s41598-020-63557-9
  • Peer Reviewed / Open Access
• [Presentation] 急性白血病のDIC診断における核内蛋白の有用性について (2020)
  • Author(s): 原田佳代, 森 博隆, 深津真彦, 佐野隆浩, 高橋裕志, 木村 哲, 大河原浩, 山田晋吾, 池添隆之
  • Organizer: 第82回 日本血液学会学術集会
• [Presentation] 血栓止血学会DIC診断基準2017を用いた凝固分子マーカーの評価 (2020)
  • Author(s): 嶋田有里, 菅野喜久子, 金子裕眠, 山寺幸雄, 池添隆之, 志村浩己
  • Organizer: 第21回 日本検査血液学会学術集会 (2020.7.11-7.12, 金沢)
• [Presentation] 血液腫瘍に合併するDICの診断における核内蛋白の有用性について (2020)
  • Author(s): 原田佳代, 森 博隆, 深津真彦, 佐野隆浩, 高橋裕志, 木村 哲, 大河原浩,山田晋吾, 池添隆之
  • Organizer: 第21回 日本検査血液学会学術集会（2020.7.11-7.12, 金沢）
• [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 (2020.6.18-6.20, 大阪)
  • 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 (2020.6.18-6.20, 大阪)
• [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 (2020.7.11-7.12, 金沢)
• [Remarks] 血液内科学講座 研究業績
  • URL: https://www.hemato.fmu.ac.jp/result/