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Parkin-dependent mitophagy in hepatic ischemia-reperfusion injury

Research Project

Project/Area Number 15K10173
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Digestive surgery
Research InstitutionJikei University School of Medicine

Principal Investigator

Yanaga Katsuhiko  東京慈恵会医科大学, 医学部, 教授 (70220176)

Co-Investigator(Kenkyū-buntansha) 白井 祥睦  東京慈恵会医科大学, 医学部, 助教 (10785364)
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords肝虚血再灌障害 / オートファジー / マイトファジー / アポトーシス / 肝虚血再灌流障害 / ミトコンドリア / Parkin / アデノウイルスベクター
Outline of Final Research Achievements

In the hepatic ischemia-reperfusion injury (IRI), mitochondria are injured by the reactive oxygen, and subsequently induces caspase signals-dependent cell apoptosis. On the other hand, the cells dissolve these dysfunctional mitochondria by mitophagy. We examined the function of Parkin protein coded by PARK2 which is the causative gene of Parkinson’s disease and plays a key role in the mitophagy. We established 70% IRI model using c57bl/6 and PARK2 K.O. mice. Inflammatory reaction and hemorrhage were observed at 1 hour (h) after reperfusion by H&E stain. Swollen abnormal mitochondria appeared at 3 h by electron microscopy. Apoptosis signals were elevated after 1 hour after reperfusion and declined in 24 h. The serum aminotransferase and parkin protein were parallel to the behavior of apoptosis signals. The serum aminotransferase levels were higher in PARK2 K.O. mice compared as that in wild type in the late phase of IRI. The hepatic IRI was enhanced under the PARK2 defect condition.

Academic Significance and Societal Importance of the Research Achievements

肝系統的切除手術では出血量制御目的で肝血流を一時的に遮断するため医原的な肝虚血再灌流傷害を引き起こす。また生体肝移植においても摘出した肝臓グラフトは必然的な虚血状態となり、移植後の肝機能傷害の原因となる。当該研究では細胞が本来持つ生体防御機構の一つであるマイトファジーに着目し、開始因子の一つであるパーキンタンパクの虚血再灌流障害における働きを明らかにした。パーキンは障害を受けたミトコンドリアの代謝に関与し、パーキンタンパク欠損状態では細胞死シグナルが増強することが判明した。そのため今後はパーキンタンパク発現を増加させるなど、肝虚血再灌流障害における新たな防御機構の開発につながる可能性がある。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (1 results)

All 2019

All Presentation (1 results)

  • [Presentation] Parkin-dependent mitophagy in hepatic ischemia-reperfusion injury2019

    • Author(s)
      白井祥睦
    • Organizer
      第31回日本肝胆膵外科学会学術集会
    • Related Report
      2018 Annual Research Report

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Published: 2015-04-16   Modified: 2020-03-30  

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