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Analyses of the mechanism for the cell death of ring sideroblasts

Research Project

Project/Area Number 21K06874
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionIwate Medical University

Principal Investigator

Furuyama Kazumichi  岩手医科大学, 医学部, 教授 (80280874)

Co-Investigator(Kenkyū-buntansha) 久保田 美子  岩手医科大学, 医学部, 准教授 (30260102)
金子 桐子  岩手医科大学, 医学部, 講師 (10545784)
鈴木 亘  岩手医科大学, 医学部, 助教 (90610395)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords遺伝性鉄芽球性貧血 / 細胞死 / ferroptosis / 疾患モデル細胞 / ゲノム編集 / 赤芽球 / モデル細胞 / 環状鉄芽球 / 鉄芽球性貧血モデル細胞 / 鉄欠乏性貧血モデル細胞 / apoptosis / 鉄芽球性貧血
Outline of Research at the Start

赤芽球の分化における無効造血のメカニズムを明らかにすることを目指す。主に解析の対象とする細胞は赤血球まで分化する培養細胞(HUDEP2細胞)で、野生型細胞をコントロールとし、ALAS2 遺伝子に変異を有するXLSAモデル細胞(XLSA細胞)、トランスフェリンの添加量を制限した培養液で維持・分化させる鉄欠乏性貧血モデル細胞 (IDA細胞)を用いる。それぞれの細胞を用いて、アポトーシス、フェロトーシスなどの細胞死がどのように関わるか、そしてミトコンドリアの機能異常やそれを除去するマイトファジーの亢進がそれらの細胞死にどのように影響するのかを観察し、無効造血と呼ばれる現象の本体を明らかにしたい。

Outline of Final Research Achievements

Congenital sideroblastic anemia (CSA) is a relatively rare disorder characterized by the presence of ring sideroblasts in a patient's bone marrow. We have previously established the CSA model cells (HA2low cells) using cultured erythroblastoid cell lines in which the ALAS2 gene was mutated by genome editing method. Using HA2low cells, we have tried to examine the cause of cell death of erythroblasts in CSA patients. After the induction of erythroid differentiation, the rate of cell death in HA2low cells is more significant than that in wild-type cells. However, the increased rate of cell death in HA2low cells during erythroid differentiation was partially rescued by the treatment with the antagonist of ferroptosis, a kind of programmed cell death caused by the oxidative stress originated by the excess cellular iron accumulation. These results suggested that ferroptosis may be one of the causes of the increase of cell death in HA2low cells and anemia observed in CSA patients.

Academic Significance and Societal Importance of the Research Achievements

遺伝性鉄芽球性貧血(CSA)は環状鉄芽球の出現を特徴とする疾患だが、環状鉄芽球の性質については不明な点が多い。本研究では、in vitroで環状鉄芽球の形成を誘導可能なモデル細胞を利用し、モデル細胞は細胞死を起こしやすい性質を有すること、その細胞死のうち少なくとも一部はferroptosis(過剰な鉄に起因する酸化ストレスが誘導する細胞死)による可能性が高いことを明らかにした。臨床的にCSA患者では鉄の過剰な蓄積が見られることが知られており、除鉄により貧血が改善する例も報告されているが、その理論的背景の説明に資する結果と考えている。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (10 results)

All 2023 2021 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (3 results) Remarks (2 results)

  • [Journal Article] <i>In vitro</i> analyses for the diagnosis of congenital sideroblastic anemia2023

    • Author(s)
      古山 和道、Kamata Costantine Chasama
    • Journal Title

      Journal of Iwate Medical Assiociation

      Volume: 75 Issue: 1 Pages: 1-9

    • DOI

      10.24750/iwateishi.75.1_1

    • ISSN
      0021-3284, 2434-0855
    • Year and Date
      2023-04-01
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Erythroid-specific 5-aminolevulinate synthase is stabilized by HSPA9 in mitochondrial matrix2023

    • Author(s)
      Costantine Chasama Kamata, Yoshiko Kubota, Kazumichi Furuyama
    • Journal Title

      Journal of Iwate Medical Assiociation

      Volume: 75 Issue: 2 Pages: 49

    • DOI

      10.24750/iwateishi.75.2_49

    • ISSN
      0021-3284, 2434-0855
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mass spectrometric analysis of erythroid specific 5-aminolevulinate synthase protein complex2023

    • Author(s)
      鈴木  亘, Costantine Chasama Kamata, 古山 和道
    • Journal Title

      Journal of Iwate Medical Assiociation

      Volume: 75 Issue: 2 Pages: 69-79

    • DOI

      10.24750/iwateishi.75.2_69

    • ISSN
      0021-3284, 2434-0855
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CLPX regulates mitochondrial fatty acid β-oxidation in liver cells2023

    • Author(s)
      Suzuki Ko、Kubota Yoshiko、Kaneko Kiriko、Kamata Costantine Chasama、Furuyama Kazumichi
    • Journal Title

      Journal of Biological Chemistry

      Volume: 299 Issue: 10 Pages: 105210-105210

    • DOI

      10.1016/j.jbc.2023.105210

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Heme‐dependent recognition of 5‐aminolevulinate synthase by the human mitochondrial molecular chaperone ClpX2021

    • Author(s)
      Nomura Kazumi、Kitagawa Yu、Aihara Marina、Ohki Yusuke、Furuyama Kazumichi、Hirokawa Takatsugu
    • Journal Title

      FEBS Letters

      Volume: 595 Issue: 24 Pages: 3019-3029

    • DOI

      10.1002/1873-3468.14214

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] CLPXはタンパク質相互作用の調節を介して肝細胞におけるミトコンドリアβ酸化を制御する2021

    • Author(s)
      金子 桐子, 久保田 美子, 鈴木 亘, 古山 和道
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] SLC25A38遺伝子変異細胞の樹立2021

    • Author(s)
      金子 桐子, 久保田 美子, 鈴木 亘, 古山 和道
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 非特異的5-アミノレブリン酸合成酵素のヘム依存的分解反応に関わる因子の同定2021

    • Author(s)
      久保田 美子, 鈴木 亘, 金子 桐子, 古山 和道
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Research-status Report
  • [Remarks] 生化学講座 [分子医化学分野]

    • URL

      https://www.iwate-med.ac.jp/education/gakubu_in/med_kouza/seika/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 岩手医科大学分子医化学分野

    • URL

      https://www.iwate-med.ac.jp/education/gakubu_in/med_kouza/seika/

    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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