| Project/Area Number |
13357011
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
General surgery
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| Research Institution | Kyushu University |
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Principal Investigator |
SHIMADA Mitsuo (2002) Surgery and Science Associate professor, 大学院・医学研究院, 助教授 (10216070)
杉町 圭蔵 (2001) 九州大学, 大学院・医学研究院, 教授 (00038762)
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| Co-Investigator(Kenkyū-buntansha) |
SOEJIMA Yuji Hospital Assistant professor, 医学部附属病院, 助手 (30325526)
SUEHIRO Taketoshi Hospital Assistant professor, 医学部附属病院, 助手 (70335967)
TANAKA Shinji Hospital Assistant professor, 医学部附属病院, 助手 (30253420)
島田 光生 九州大学, 医学部・附属病院, 講師 (10216070)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥51,350,000 (Direct Cost: ¥39,500,000、Indirect Cost: ¥11,850,000)
Fiscal Year 2002: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2001: ¥39,650,000 (Direct Cost: ¥30,500,000、Indirect Cost: ¥9,150,000)
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| Keywords | super liver graft / gene-transfer / electroporation / telomerase reverse transcriptase / ischemia-reperfusion / small-for-size graft / Rho-kinase / テロメラーゼ逆転写酵素 / 虚血再灌流傷害 / 障害耐性肝移植グラフト / 遺伝子導入肝グラフト / TNFαアンチセンス遺伝子 / テノメラーゼ逆転写酵素遺伝子 / 虚血再灌流障害 |
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| Research Abstract |
This study was conducted to clarify the mechanism of ischemia-reperfusion (I/R) injury or small-for-size graft (SSG) injury, and to create a super liver graft resistant to various kinds of injuries using a gene-transfer technique.
(1) Development of gene-transfer technique :
Instead of retrovirus vector with critical risk of leukemia (Science 2002), electroporation-mediated gene transfer to cold preserved graft was carried out, using a new instrument designed for a rat liver graft. Using a combined method of electroporation and hydrodynamic (=positive pressure to the portal vein) technique, luciferase-gene expression in the graft after liver transplantation was found to be increased. But a significant graft damage was also observed. A new gene-transfer method using nano-carrier is, therefore, now applied.
(2) Liver transplant (LT) model using a small-for-size graft :
In a new rat LT model using small-for-size graft (SSG : 30% of whole liver volume), survival of transplanted rats was suggested to prolong either by either creation of partial porto-systemic shunt (splenopexy beneath the skin) or administration of somatostatin analogue having effect of reduced portal pressure. Therefore, excessive portal perfusion of SSG was proved to be a critical cause of SSG injury. A new LT model was, furthermore, completed in mice.
(3) Role of Rho-kinage on ischemia-reperfusion injury :
Rho-kinase, a molecular substance related to vascular contraction or neutrophil migration, was found to played an important role on I/R injury. Its inhibitor (Fasudil) inhibited cytokine production (TNFa and IL1b) and free radical production in I/R injury. By administration of Fasudil, postoperative elevation of AST and ALT, and necrotic areas in the specimen, were reduced, furthermore, rat's survival rate after LT improved in a 24-hour cold-preserved LT model. Either anti-sense or dominant negative of Rho-kinase gene is now applied to liver graft using a non-viral gene-transfer technique.
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