| Project/Area Number |
16K10090
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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 |
Embryonic/Neonatal medicine
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | ダウン症候群 / iPS細胞 / 造血異常 / TAM / ゲノム編集 / ゲノム編集技術 / 染色体異常 |
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| Outline of Final Research Achievements |
Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genomeediting technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究において、ダウン症候群の新生児に頻発し高い頻度で重篤化する一過性骨髄異常増殖症（TAM）の発症メカニズムを明らかにし、さらにその責任遺伝子を同定することができた。これによりTAMの診断・治療法の開発が進むと思われる。さらに、今回我々が作成したiPS細胞疾患モデルは、前白血病段階から白血病へと進む造血性腫瘍の多段階発症メカニズムの解明に役立つと思われ、今後白血病の治療法開発へとつながると期待される。
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