A critical role of Gas6-TAM signaling pathway in the pathology of HSCT-associated TMA

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08366
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Ogawa Kazuei 福島県立医科大学, 医学部, 教授 (40423800)
• Co-Investigator(Kenkyū-buntansha): 大河原 浩 福島県立医科大学, 医学部, 准教授 (10381360) ; 池添 隆之 福島県立医科大学, 医学部, 教授 (80294833)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: Gas6 / Mer / 造血幹細胞移植 / 移植後TMA

Outline of Final Research Achievements

Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family. Serum Gas6 levels were significantly increased in HSCT patients with transplant-associated thrombotic microangiopathy (TA-TMA), and Gas6 and a selective Mer tyrosine kinase (Mer) expression levels were upregulated in TA-TMA lesions of liver and kidney. In human umbilical vein endothelial cells (ECs),the exposure of sera isolated from patients with aute GVHD to ECs induced the downregulation of thrombomodulin, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, UNC2250 treatment suppressed TA-TMA in these mouse HSCT models.

Free Research Field

同種造血幹細胞移植

Academic Significance and Societal Importance of the Research Achievements

本研究は移植後TMAの病態解明に寄与するとともに、 Gas6-Merシグナルが新たな治療標的候補や新規バイオマーカーとなることを示した。我々の研究成果は新たな創薬や検査法の開発に大きく貢献できる可能性を秘めている。我々の研究成果は新たな創薬や検査法の開発に大きく貢献できる可能性を秘めている。これらの研究結果は2018年10月日本血液学会総会（大阪）、2018年12月米国血液学会学術集会(サンディエゴ)にて発表した。研究成果は米国科学雑誌Blood Advancesに掲載された(Blood Adv.2019;3(14):2128-2143.)。