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Investigation of disease mechanisms in hematopoietic abnormalities in Down syndromI

Research Project

Project/Area Number 16K10090
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Embryonic/Neonatal medicine
Research InstitutionOsaka University

Principal Investigator

Kitabatake Yasuji  大阪大学, 医学部附属病院, 准教授 (80506494)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
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)
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
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.

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。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (3 results)

All 2019 2016

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (1 results)

  • [Journal Article] Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts2019

    • Author(s)
      Nawa Nobutoshi、Hirata Katsuya、Kawatani Keiji、Nambara Toshihiko、Omori Sayaka、Banno Kimihiko、Kokubu Chikara、Takeda Junji、Nishimura Ken、Ohtaka Manami、Nakanishi Mahito、Okuzaki Daisuke、Taniguchi Hidetoshi、Arahori Hitomi、Wada Kazuko、Kitabatake Yasuji、Ozono Keiichi
    • Journal Title

      PLOS ONE

      Volume: 14 Issue: 7 Pages: 0219592-0219592

    • DOI

      10.1371/journal.pone.0219592

    • NAID

      120007133008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Systematic cellular disease models reveal synergistic interactions of trisomy 21 and GATA1 mutations in hematopoietic abnormalities2016

    • Author(s)
      K. Banno, S. Omori, K. Hirata, N. Nawa, N. Nakagawa, K. Nishimura, M. Ohtaka, M. Nakanishi, T. Sakuma, T. Yamamoto, T. Toki, E. Ito, T. Yamamoto, C. Kokubu, J. Takeda, H. Taniguchi, H. Arahori, K. Wada, Y. Kitabatake and K. Ozono
    • Journal Title

      Cell Reports

      Volume: 15 Issue: 6 Pages: 1-15

    • DOI

      10.1016/j.celrep.2016.04.031

    • NAID

      120007135439

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 疾患iPS細胞とゲノム編集をもちいたダウン症候群におけるTAMの病態解析2016

    • Author(s)
      北畠康司,坂野公彦,大森早也佳,平田克弥,那波伸敏,中川夏季,谷口英俊,荒堀仁美,和田和子,大薗惠一
    • Organizer
      第119回 日本小児科学会
    • Place of Presentation
      札幌
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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