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Mechanism by which deficiency of hematopoietic stem cell antigen ESAM leads to lethal erythropoietic failure during fetal life

Research Project

Project/Area Number 19K08863
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionOsaka University

Principal Investigator

Ueda Tomoaki  大阪大学, 医学系研究科, 助教 (60747517)

Co-Investigator(Kenkyū-buntansha) 柴山 浩彦  大阪大学, 医学系研究科, 招へい教授 (60346202)
横田 貴史  大阪大学, 医学系研究科, 准教授 (60403200)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords造血幹細胞 / 血管内皮細胞 / ESAM / 造血発生 / 胎仔肝 / 赤血球造血
Outline of Research at the Start

胎生期造血における血管内皮関連抗原endothelial cell-selective adhesion molecule (ESAM)の機能的意義を分子レベルで明らかにする。まずはESAM欠損によって、赤血球造血の発生がどのような影響を受けるのかを詳細に解明する。つぎに、ESAM欠損が引き起こす異常のメカニズムを、細胞・分子レベルで解析する。造血幹細胞・血管内皮細胞それぞれにおけるESAMの役割をより明確にするため、申請者らで独自に作製した条件付きESAM欠損マウスを用いる。

Outline of Final Research Achievements

To elucidate the functional significance of Endothelial cell-selective adhesion molecule (ESAM) in the development of hematopoiesis, we analyzed fetuses from conventional or conditional ESAM-knockout mice. Approximately half of ESAM-null fetuses died after mid-gestation. RNA-seq revealed downregulation of adult-type globins and Alas2 in ESAM-null fetal livers. These abnormalities were attributed to malfunction of ESAM-null hematopoietic stem cells, which was demonstrated in culture and transplantation experiments. Analysis of conditional ESAM-knockout fetuses revealed the critical involvement of ESAM expressed in endothelial cells in fetal lethality.

Academic Significance and Societal Importance of the Research Achievements

ESAM 欠損マウス、独自に作製した条件付き ESAM 欠損マウスを解析することにより、ESAM が胎生期の造血機構の発生、特に成体型ヘモグロビン合成に重要で、ESAM 欠損により高率に胎生後期死亡をきたすことを明らかにした。また、造血幹細胞のみならず血管内皮細胞の ESAM も造血発生に寄与することがわかった。
本研究成果により、造血発生の仕組み、特に赤血球造血に関する理解が深まると考えられる。再生医療や遺伝子治療を通じて、遺伝性貧血など先天性の造血器疾患の治療法開発への基盤となることが期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (3 results)

All 2021 2020 2019

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results)

  • [Journal Article] Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia2021

    • Author(s)
      Yasuhiro Shingai , Takafumi Yokota,et al
    • Journal Title

      Stem cells

      Volume: - Issue: 6 Pages: 723-736

    • DOI

      10.1002/stem.3348

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy2020

    • Author(s)
      Tomoaki Ueda, Tomoyasu Jo, Kazuya Okada, Yasuyuki Arai, Takayuki Sato, Takeshi Maeda, Tatsuhito Onishi, Yasunori Ueda
    • Journal Title

      Int J Hematol

      Volume: 111 Issue: 2 Pages: 247-255

    • DOI

      10.1007/s12185-019-02763-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver2019

    • Author(s)
      Ueda Tomoaki、Yokota Takafumi、Okuzaki Daisuke、Uno Yoshihiro、Mashimo Tomoji、Kubota Yoshiaki、Sudo Takao、Ishibashi Tomohiko、Shingai Yasuhiro、Doi Yukiko、Ozawa Takayuki、Nakai Ritsuko、Tanimura Akira、Ichii Michiko、Ezoe Sachiko、Shibayama Hirohiko、Oritani Kenji、Kanakura Yuzuru
    • Journal Title

      Stem Cell Reports

      Volume: 13 Issue: 6 Pages: 992-1005

    • DOI

      10.1016/j.stemcr.2019.11.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access

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Published: 2019-04-18   Modified: 2023-01-30  

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