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Basic research and clinical approach of molecular therapy for liver cirrhosis and HCC

肝硬化和肝癌分子治疗的基础研究和临床途径

基本信息

批准号：
14370395
负责人：
FUJIMOTO Jiro
金额：
$ 7.62万
依托单位：
HYOGO COLLEGE OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370395/
关键词：
Liver cirrhosis Hepatoma HGF BMT GVHG Gene therapy 肝再生

项目摘要

Liver cirrhosis has been regarded to be irreversible end of fibrous scaring with no effective therapy up to now. We recently established a novel gene therapy approach for rat liver cirrhosis by HVJ-liposome mediated muscle-directed gene transfer of hepatocyte growth facor(HGF). We also reported novel gene therapy for hepatoma. In this study, we performed following several experiments to apply these molecular therapy for human liver cirrhosis and hepatoma : 1)analysis of detail mechanism of HGF mediated anti-fibrogenesis 2)bone marrow-derived cells participate in the remodeling process of liver fibrosis with HGF gene therapy 3)BMT mediated graft-versus-tumor effect against hepatoma.As the result of these experiments, we got much novel findings. HGF mediated anti-fibrogenesis was thought to act the enhancement of MMP expression by HGF rather than the suppression of TGFβ1 by activation of HGF in Kuppfer cells. When HGF acts in NK cell in vitro, TGFβ1 was suppressed in mRNA and protein level. Bone marrow-derived cells appeared to participate in the remodeling process of liver fibrosis and HGF gene delivery accelerated this recruitment. As the most of bone marrow-derived cell were detected as endothelial cells, reconstruction of blood vessels seemed significantly important for recovery process of liver fibrosis. BMT with HGF therapy markedly inhibited growth of hepatoma. Moreover, HGF ameliorates GVHD effect that is main side effect of BMT.These results suggested that these molecular therapy is capable for treatment of human liver cirrhosis and hepatoma.

肝硬化被认为是纤维疤痕的不可逆转的终结，迄今为止还没有有效的治疗方法。我们最近通过 HVJ 脂质体介导的肝细胞生长因子 (HGF) 肌肉定向基因转移建立了一种针对大鼠肝硬化的新型基因治疗方法。我们还报道了肝癌的新型基因疗法。在本研究中，我们进行了以下几项实验，将这些分子疗法应用于人类肝硬化和肝癌：1）HGF介导的抗纤维形成的详细机制分析2）骨髓来源细胞通过HGF基因治疗参与肝纤维化的重塑过程3）BMT介导的移植物抗肿瘤作用对抗肝癌。我们得到了很多新奇的发现。 HGF 介导的抗纤维发生被认为是通过 HGF 增强 MMP 表达，而不是通过激活 Kuppfer 细胞中的 HGF 来抑制 TGFβ1。当HGF在体外作用于NK细胞时，TGFβ1的mRNA和蛋白水平受到抑制。骨髓来源的细胞似乎参与了肝纤维化的重塑过程，而 HGF 基因的传递加速了这种招募。由于大多数骨髓来源的细胞被检测为内皮细胞，血管的重建对于肝纤维化的恢复过程显得非常重要。 BMT联合HGF治疗显着抑制了肝癌的生长。此外，HGF还改善了BMT的主要副作用GVHD效应。这些结果表明这些分子疗法能够治疗人类肝硬化和肝癌。