| Project/Area Number |
09470262
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Digestive surgery
|
|---|
| Research Institution | Gunma University |
|---|
Principal Investigator |
KOGURE Kimitaka Gunma University School of Medicine, Assistant Professor, 医学部, 講師 (80143220)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KOJIMA Itaru Institute for Molecular and Cellular Regulation Gunma University, Department of Cell Biology, Professor, 生体調節研究所, 教授 (60143492)
|
|---|
| Project Period (FY) |
1997 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1997: ¥10,300,000 (Direct Cost: ¥10,300,000)
|
|---|
| Keywords | activin A / follistatin / TGF-β / liver regeneration / adenovirus vector / dominant negative receptor of activin A / gene transfer / virus vector / TGF-β受容体 / ペプチド合成 |
|---|
| Research Abstract |
Augmentation of liver regeneration, with an artificial support to maintain liver function necessar for survival, would be beneficial for the treatment of fulminant hepatic failure caused by viral infection and hepatic toxins. As well, massive hepatectomy to resect liver tumors can be performed safely if the growth of the remnant liver is promoted effectively. Recently, the roles of various growth factors in the regulation of hepatocyte growth have been elucidated. Activin A which belongs to the transforming growth factor β super gene family is a potent autocrine growth inhibitor in hepatocytes. Activin A is induced in vivo after partial hepatectomy. Low levels of the messenger RNA for the bA-subunit of activin are markedly increased 20 hours after hepatectomy. When follistatin, which binds activin and blocks its action, is infused into the portal vein immediately after hepatectomy of 70 %, DNA is synthesized several hours earlier than in control rats and liver regeneration is significa
… More
ntly augmented. Follistatin provides a potential therapeutic approach to promoting liver regeneration because it specifically blocks autocrine growth inhibitor. The results were reported in Gastroenterology (vol 108 : 1136-1142, 1995). Then, we obtained the results that the intravenous administration of follistatin effectively promoted liver regeneration after partial hepatectomy. These were reported in Hepatology (vol : 24 : 361-366, 1996). We then investigated the effects of follistatin on liver regeneration under more critical condition, 90 % hepatectomy in rats and obtained the results that follistatin was quite effective in promoting liver regeneration (J Hepatol 29: 977-984, 1998). This raises the possibility that liver regeneration may be accelerated by the internal blockade of the autocrins of the autocrine actions of activin and TGF-β. The present study was conducted to address this issue. For this purpose, we constructed the dominant negative activin and TGF-β receptors on the hepatocytes. The adenovirus (5-dlX) vector was transferred with dominant negative activin and TGF-β type II receptors and cultured in the 293 cells. The virus vector was directly injected via the portal vein into the liver of rats and DNA synthesis was analyzed by measuring labeling index of BrDU and the DNA content. As a control, adenovirus which was transferred lacZ gene was also injected directly via the portal vein into hepatocytes and the β-galactosidase activity was analyzed by measuring the staining index of 5-bromo-4-chloro-indolyl-b-D-galactoside. We are investigating the effects of the dominant negative activin and TGF-β type II receptors expressed on the hepatocytes for liver regeneration. Less
|
