| Project/Area Number |
18K07810
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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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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Hirosaki University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
土岐 力 弘前大学, 医学研究科, 講師 (50195731)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ダウン症候群 / 一過性異常骨髄増殖症 / GATA1 / 好酸球増多症 / 肝障害 / 遺伝子変異 |
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| Outline of Final Research Achievements |
We performed this study to clarify effects of GATA1 mutation types on eosinophilia and liver dysfunction in infants with Down syndrome and TAM and obtained following results.
1. We introduced various GATA1 mutations into a human leukemia cell line and found that expression levels of GATA1s protein depended on GATA1 mutation types. GATA1s-low clones expressed GATA2 and KIT mRNAs at higher levels than GATA1s-high clones, suggesting that the former was more immature than the latter.
2. We performed RNA-sequencing using samples of infants with TAM and analyzed gene expression profiling. We found a patient population expressing megakaryocytic genes at higher levels and all these patients had liver dysfunction. These megakaryocytic genes included several cytokines related to pathogenesis of liver fibrosis suggesting association between high expression of these cytokines and liver dysfunction.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでの研究により、ダウン症のTAMにおいて、GATA1変異のタイプにより肝障害を合併する頻度が異なることは分かっていたが、その機序は不明であった。本研究により、GATA1変異のタイプによりGATA1sタンパクの発現レベルが異なり、その違いが転写因子の発現レベルや巨核球系への分化度に影響することが明らかになった。さらに、巨核球関連遺伝子群の高発現と肝障害との関連も明らかになった。GATA1変異解析により、肝障害の高危険群を正確に同定できるようになれば、肝障害の早期治療や予防に応用できる可能性がある。また、肝障害の原因になるサイトカインを同定できれば、より効果的な治療が可能になるかもしれない。
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