Study on gene therapy for liver regeneration. -Effect of gene transduction of soluble HB-EGF and soluble TGF-β type II receptor on liver regeneration-

• Project/Area Number: 13670517
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TAMURA Shinji Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30243223)
• Co-Investigator(Kenkyū-buntansha): IGURA Takumi Osaka University Hospital, Medical Staff, 医学部附属病院, 医員(臨床研究) ; FUKUI Koji Osaka University Hospital, Medical Staff, 医学部附属病院, 医員(臨床研究) ; KISO Shinichi Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40335352) ; 土井 喜宣 大阪大学, 医学部・附属病院, 医員
• Project Period (FY): 2001 – 2002
• Project Status: Completed(Fiscal Year 2002)
• Budget Amount: ¥3,000,000 (Direct Cost : ¥3,000,000); Fiscal Year 2002 : ¥1,200,000 (Direct Cost : ¥1,200,000); Fiscal Year 2001 : ¥1,800,000 (Direct Cost : ¥1,800,000)
• Keywords: liver regeneration / soluble receptor / soluble HB-EGF / TGF-β / gene therapy / 可溶性TGF-βII型受容体 / 可溶型HB-EGF / HVJ-リポソーム

Research Abstract

Acceleration of liver regeneration is important for the treatment of hepatic failure. We have reported that HB-EGF is a potent mitogen of hepatocyte and plays an important role in liver regeneratian. On the other hands, TGF-β, a growth inhibitory factor stimulates apoptosis of hepatocyte and inhibits liver regeneration.
In this study, we demonstrated that NF-kB is activated in hepatic non-parenchymal cells after partial hepatectomy and stimulates the expression of HB-EGF gene. We also indicated that soluble form of HB-EGF is essential for liver regeneration using HB-EGF transgenic mice.
To develop the new methods for acceleration the liver regeneration, dual introduction of soluble HB-EGF gene and soluble TGF-βtype II receptor that blocks the action of TGF-β is investigated. We developed the expression plasmid containing soluble TGF-βtype II receptor cDNA attached with human immunoglobulin Fc region or soluble HB-EGF cDNA. Both genes were introduced into mice skeletal muscle using in vivo electroporation methods. The plasma concentration of soluble HB-EGF and soluble TGF-β type II receptor were measured with newly developed ELISA systems. Pretreatment with hyaluronidase increased the expression levels and obtains 6-fold higher concentrations of soluble HB-EGF or soluble TGF-βtype II receptor.
Our results give a basis for development of the gene therapy to accelerate the liver regeneration.

Research Products

• [Publications] S.Sakuda, S.Tamura, et al.: "NF-kappaB activation in non-parenchymal liver cells after partial hepatectomy in rats : possible involvement in expression of heparin-binding epidermal growth factor-like growth factor"J. Hepatol.. 36. 527-533 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] S.Sakuda, S.Tamura, et al.: "Activation of signal transducer and activator of transcription 3 and expression of suppressor of cytokine signal 1 during liver regeneration in rats"J. Hepatol.. 36. 378-384 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] S.Kiso, et al.: "Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy"Gastroenterology. 124. 701-707 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] S. Sakuda, S. Tamura, A. Yamada, J. Miyagawa, K. Yamamoto, S. Kiso, N. Ito, S. Higashiyama, N. Taniguchi, S. Kawata, Y. Matsuzawa: "NF-kappaB activation in non-parenchymal liver cells after partial hepatectomy in rats: possible involvement in expression of heparin-binding epidermal growth factor-like growth factor"J Hepatol.. 36(4). 527-533 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] S. Sakuda, S. Tamura, A. Yamada, J. Miyagawa, K. Yamamoto, S. Kiso, N. Ito, K. Imanaka, A. Wada, T. Naka, T. Kishimoto, S. Kawata, Y. Matsuzawa: "Activation of signal transducer and activator transcription 3 and expression of suppressor of cytokine signal 1 during liver regeneration in rats"J Hepatol.. 36(3). 378-384 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] S. Kiso, S. Kawata, S. Tamura, Y. Inui, Y. Yoshida, Y. Sawai, S. Umeki, N. Ito, A. Yamada, J. Miyagawa, S. Higashiyama, T. Iwawaki, M. Saito, N. Taniguchi, Y. Matsuzawa, K. Kohno: "Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy"Gastroenterology. 124(3). 701-707 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kiso S, Kawata S, et al.: "Transgenic expression of heparin-binding EGF-like growth factor in the mice liver accelerates the proliferation oh hepatocytes after partial hepatectomy"Gastroentreology. (in press). (2003)
• [Publications] Sakada S, Tamura S, et al.: "NF-kappaB activation an non-parenchymal liver cells after partial hepatectomy in rats : possible involvement in expression of heparin-binding epidermal growth factor-like growth factor"J Hepatol. 36・4. 527-533 (2001)
• [Publications] Sakuta S, Tamura S et al.: "NF-kB activation in non-parenchymal liver cells after partial hepatectomy in rats : possible involvement in expression of heparin-binding epidermal growth factor-like growth factor"J. Hepatology. (in press). (2001)
• [Publications] Sakuta S, Tamura S et al.: "Activation of signal transducer and activator transcription 3 and expression of suppressor of cytokine signal 1 during liver regeneration in rats"J. Hepatology. (in press). (2001)