The analysis of mechanism for mitochondrial iron accumulation on sideroblastic anemia model cells

• Project/Area Number: 17K09910
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Iwate Medical University
• Principal Investigator: Kaneko Kiriko 岩手医科大学, 医学部, 講師 (10545784)
• Co-Investigator(Kenkyū-buntansha): 古山 和道 岩手医科大学, 医学部, 教授 (80280874)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 鉄代謝 / ヘム合成 / 赤血球分化 / ミトコンドリア / 鉄芽球性貧血

Outline of Final Research Achievements

This study tried to establish model cells for sideroblastic anemia and analyze for elucidation of the iron accumulation mechanism in congenital sideroblastic anemia (CSA). To establish model cell, SLC25A38 and GLRX5, a kind of CSA responsible genes, were inserted mutation its genomic DNA using CRISPR-Cas9 system. And these cells were observed sideroblast after differentiation. The characters of these mutated cells were similar to ALAS2 mutated cells. As the analyze for iron accumulation mechanism, the result of induction of DMT1 expression in HA2low1 cells suggested that iron import may enhance on CSA model cells.

Academic Significance and Societal Importance of the Research Achievements

本課題の成果として樹立した細胞は鉄芽球性貧血における鉄蓄積機構の解明を目的とした。すでに樹立に成功、報告したALAS2変異細胞であるHA2low1細胞について、国内外の研究者より分与依頼を受けた。これまでに培養細胞において鉄蓄積を誘導できる細胞株がなかったことから、鉄芽球性貧血貧血のみならず、赤芽球分化研究のツールのひとつとして有用である可能性が考えられた。赤芽球系の疾患は血液系の中でも大きな割合ではないが、確かに存在する疾患の治療への一助となりうる疾患モデル細胞のひとつとして樹立できた成果は学術的のみならず、社会的にも貢献できることが期待される。

Research Products

• [Journal Article] ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration (2019)
  • Author(s): Takuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Feraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Al Bacha Jeanne d'arc, Hiroshi Yamada et al.
  • Journal Title: Journal of Clinical Investigation Volume: 130 Issue: 5 Pages: 2145-2162
  • DOI: 10.1172/jci79990
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of a cell model of X-linked sideroblastic anemia using genome editing. (2018)
  • Author(s): Kaneko K, Kubota Y, Nomura K, Hayashimoto H, Chida T, Yoshino N, Wayama M, Ogasawara K, Nakamura Y, Tooyama I, Furuyama K
  • Journal Title: Exp Hematol Volume: 65 Pages: 57-68
  • DOI: 10.1016/j.exphem.2018.06.002
  • Peer Reviewed
• [Journal Article] Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia (2017)
  • Author(s): Furuyama Kazumichi、Kaneko Kiriko
  • Journal Title: International Journal of Hematology Volume: 107 Issue: 1 Pages: 44-54
  • DOI: 10.1007/s12185-017-2368-0
• [Presentation] ミトコンドリア内ヘム依存的ALAS1分解の調節機構 (2019)
  • Author(s): 久保田美子, 金子桐子, 鈴木亘, Kamata Costantine Chasama, 古山和道
  • Organizer: 第92回日本生化学会大会
• [Presentation] 赤芽球における鉄蓄積機構解析 (2018)
  • Author(s): 金子桐子
  • Organizer: 第91回 日本生化学会年会
  • Invited
• [Presentation] ALAS2変異による遺伝性鉄芽球性貧血のモデル細胞樹立 (2017)
  • Author(s): 金子桐子
  • Organizer: 2017年度生命科学系合同年次大会 第90回日本生化学会大会 第40回日本分子生物学会