2018 Fiscal Year Final Research Report

Novel mutation search of antithrombin resistance and its pathological analysis research by mouse model

Research Project

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Project/Area Number	16K09825
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Hematology
Research Institution	Nagoya University
Principal Investigator	Kojima Tetsuhito 名古屋大学, 医学系研究科(保健), 教授 (40161913)
Co-Investigator(Kenkyū-buntansha)	高木明名古屋大学, 医学系研究科(保健), 准教授 (30135371) 松下正名古屋大学, 医学部附属病院, 教授 (30314008)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	アンチトロンビン・レジスタンス（ATR） / プロトロンビン / 遺伝子異常 / ATR検出・臨床検査法 / 自動化機器 / ATR残存凝固活性 / Na+結合領域 / Arg593Leuノックインマウス
Outline of Final Research Achievements	We have reported dis-prothrombinemia (R596L) showing a novel thrombotic tendency, antithrombin resistance (ATR), and further established the ATR detection test and identified a different mutation (R596Q). In addition, as a result of examining the coagulation activity characteristics of single base substitution mutants in the Na+ binding domain amino acids, K599R and E592Q showed ATR residual coagulation activity equivalent to the reported mutations. Furthermore, although R593L (corresponding to human R596L) knock-in mice showed normal birth and exhibited ATR, the antigen amount of prothrombin was as low as 70%, the one-step coagulation activity was 35%, and the ATR residual coagulation activity was relatively low compared to R596L mutant in human, R593L mutant homozygous mice seemed to have a low risk of thrombosis.
Free Research Field	血液内科、血栓止血学領域
Academic Significance and Societal Importance of the Research Achievements	静脈血栓塞栓症の遺伝子異常判明例の約2/3は原因特定に至っていない中、申請者らが世界で初めて報告した新たな血栓性素因概念アンチトロンビン・レジスタンス（ATR）の遺伝子異常を検索・解析は、従来にない独創的な発想の研究である。本研究は、これまで原因特定に至ってない症例でのATR血栓性素因の同定とその詳細な病態解析、遺伝子組換体による新たなATR遺伝子異常の同定解析、ATRマウスの血栓症発症病態解析を行うもので、加齢とともに増加する深部静脈血栓・肺塞栓症の新しい診断法や予防法、治療法の開発に極めて有用な情報を提供することが予想され、超高齢化社会を迎えつつある日本において大きな社会的意義をもつ。