Treatment of sepsis with exosomal thrombomodulin

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08917
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Mie University
• Principal Investigator: KAWAMOTO EIJI 三重大学, 医学部附属病院, 講師 (20577415)
• Co-Investigator(Kenkyū-buntansha): 江口 暁子 三重大学, 医学系研究科, 特任講師(研究担当) (00598980) ; 島岡 要 三重大学, 医学系研究科, 教授 (40281133) ; 高娃 阿栄 三重大学, 医学系研究科, 助教 (50643805)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: トロンボモジュリン / 敗血症 / Fc融合蛋白 / エキソソーム

Outline of Final Research Achievements

We created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell ad-hesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca2+ and Mg2+ but not under strong integrin-activation conditions in the presence of Mg2+ without Ca2+.

Free Research Field

敗血症

Academic Significance and Societal Importance of the Research Achievements

我々の知見は、炎症の比較的早い段階で外因性に投与されるthrom-bomodulin Fc融合タンパク質が、乳癌細胞株のβ1インテグリンとフィブロネクチンの結合を阻害する新しい治療法の開発に応用できることを示唆している。
本研究のようなTM-Fc型の安定化した蛋白の知見はエキソソーム型トロンボモジュリンの開発に役立てることができる。