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Mechanism of liver regeneration from the viewpoints of cytotoxis activity and cell growth factors, and development of a method for enhancement of liver regeneration using glutamine

从细胞毒活性和细胞生长因子的角度研究肝再生的机制以及使用谷氨酰胺促进肝再生的方法的开发

基本信息

批准号：
11671286
负责人：
NAKAI Takuya
金额：
$ 1.15万
依托单位：
Kinki University School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671286/
关键词：
liver regeneration CTRactivity NK activity NKT cell glutamine transcriotion factor DNAマイクロアレイ

项目摘要

Recently, the mechanism of liver regeneration has been studied using the immunological approach. In a hepatectomy model, appearance of self-injuring lymphecytes, accelerated expression of MHC antigens, and infiltration of CD8-positive cells in the liver had been demonstrated in an early stage of regeneration. In our study of transplantion of small intestine, migration of graft-antigen presenting cells into the liver via the portal vein and rejecting reaction there were observed. In these points, the environment for intestine grafting seems to be similar to that for liver regeneration, and an immunological organ-correlation between the liver and the small intestine was demonstrated. Therefore, we considered that liver regeneration phenomenon is a rejecting reaction against self-hepatocytes. However, in a hepatectomy model, no difference was found between the small intestine and the liver at the time of liver regeneration with respect to the dynamics of CTL, NK activity or NKT cells that sho specific distribution in the small intestine and the liver. On the other hand, as clinical application of liver-regeneration enhancement therapy, a hepatectomy model was fed with food containing glutamine at different concentration (0, 2 or 4%). Consequently, on the 7th day after operation, LBR (ratio of weight of the remaining liver to that of body weight) that indicates lliver regeneration in the 2% group was higher than that in the 0% or 4$ group. Since NK activity was significantly high in the 2% group in comparison with that in the 0% and 4% groups, the optimum glutamine concentration was 2%. For the purpose of demonstrating the mechanism of liver regeneration in vivo, cell-growth factors, cell-cycle control factors and transcription-regulating factors pertaining to liver regeneration were examined using a DNA expressions in a short time in analyses of cancer-related genes. Consequently, activation of transcription factors such as STAT3, C/EBPs, Bel-x and IGF was suggested.

近年来，肝再生的机制已被应用免疫学方法研究。在肝切除模型中，在再生的早期阶段，已经证明了自伤淋巴细胞的出现、MHC抗原的加速表达以及肝脏中CD 8阳性细胞的浸润。在我们的小肠移植研究中，观察到移植物抗原提呈细胞经门静脉向肝内迁移，并在肝内发生排斥反应。在这些方面，肠移植的环境似乎与肝再生的环境相似，并且证明了肝脏和小肠之间的免疫器官相关性。因此，我们认为肝再生现象是对自体肝细胞的排斥反应。然而，在肝切除模型中，在肝脏再生时，在小肠和肝脏之间没有发现关于CTL、NK活性或NKT细胞的动力学的差异，所述CTL、NK活性或NKT细胞在小肠和肝脏中具有特异性分布。另一方面，作为肝再生促进疗法的临床应用，用含有不同浓度（0、2或4%）的谷氨酰胺的食物喂养肝切除模型。因此，在手术后第7天，2%组中指示肝再生的LBR（剩余肝的重量与体重的比率）高于0%或4%组。由于2%组的NK活性显著高于0%和4%组，因此最佳谷氨酰胺浓度为2%。为了证明体内肝再生的机制，在癌症相关基因的分析中，使用短时间内的DNA表达来检查与肝再生有关的细胞生长因子、细胞周期控制因子和转录调节因子。因此，转录因子如STAT 3、C/EBP、Bel-x和IGF的激活被提出。