| Project/Area Number |
15K10173
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Digestive surgery
|
|---|
| Research Institution | Jikei University School of Medicine |
|---|
Principal Investigator |
|
|---|
| 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。
|
