| Project/Area Number |
17K09959
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
小川 一英 福島県立医科大学, 医学部, 教授 (40423800)
池添 隆之 福島県立医科大学, 医学部, 教授 (80294833)
池田 和彦 福島県立医科大学, 医学部, 教授 (90381392)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2019: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | Gas6 / 同種造血幹細胞移植 / Mer / 内皮障害 / 造血幹細胞移植 / GVHD / TA-TMA / 移植片対宿主病 / 血栓性微小血管障害症 |
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| Outline of Final Research Achievements |
Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a pathology of graft-versus-host disease (GVHD), which are serious complications of HSCT. Serum Growth arrest-specific (Gas) 6 s levels were significantly increased in HSCT patients with acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis of the liver. Of note, intravenous administration of UNC2250 markedly suppressed GVHD in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for GVHD.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究はGVHD及びTA-TMA病態の一端を解明し、 Gas6-MerシグナルがGVHD及びTA-TMAに対する新たな治療標的や検査法開発に寄与する可能性を秘めている。本研究成果は米雑誌Blood Advances (Blood Adv. 2019;3(14):2128-2143.)に掲載された。
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