Molecular Analysis of liver cirrhosis

为了在日本开发肝硬化的新治疗方法，有必要研究肝硬化的分子机制。由于肝硬化被认为是肝再生过程中的一种形态发生障碍，因此本课题主要集中在组织再生的转录调控机制和细胞因子表达方面。在前者中，我们研究了丁酸对分化的肝癌细胞系甲胎蛋白（AFP）和白蛋白基因表达的影响。第二部分分析了甲状旁腺激素相关肽（PTHrP）在形态发生和肿瘤发生中的病理生理作用，对AFP上游调控元件的研究阐明了CCAAT盒在AFP向白蛋白基因表达转换机制中的重要作用。这些数据推测涉及肝硬化的基因可能受C/EBP控制（Gastroenterology 107：499- 504，1994）。 ...更多信息 在艾弗再生中，PTHrP是调节细胞运动和凋亡的关键细胞因子（Endocrinology 134：1936- 1942，1994. Arterioscl Throm Vascul Biol in press 1996）。PTHrP表达的增加也被证明涉及其它器官中的纤维化（J Pathol 175：227-236，1995）。此外，我们还应用PTHrP反义寡核苷酸治疗了本实验室新建立的PTHrP分泌型垂体瘤（癌症研究56：77- 86，1996）。为了进一步扩展基础研究，我们集中于由逃避生理再生或凋亡的细胞因子的异常表达诱导的肝硬化的关键事件，其最终可诱导基因不稳定和异常细胞增殖。实验设计是体内大鼠动物模型，其被植入先前描述的产生PTHrP的垂体瘤。令人惊讶的是，这些大鼠在接种肿瘤细胞后3个月内发生了肝纤维化和脾肿大，并且在肿瘤植入后4个月也发生了肝癌。我们计划利用这种体内实验系统进一步研究细胞因子诱导肝硬化的分子机制。最后，我们感谢这笔资助以及我们的博士后研究员和工作人员的宝贵贡献。少

To develop the new treatment of liver cirrhosis in Japan, it is essential to investigate on the molecular mechanism of liver cirrhosis. In the present projects, we have concentrated in the transcriptional control mechanism and cytokine expression of tissue regeneration, because liver cirrhosis is thought to be a kind of dis-regurated morphogenesis in the liver regeneration. In the former, we have studied the effect of butyrate in alpha-fetoprotein (AFP) and albumin gene expression using the differentiated liver cancer cell lines. In the later, we have analyzed the pathophysiological role of parathyroid-hormone-related peptide (PTHrP) in morphogenesis and oncogenesis.The study of upstream regulatory element of AFP has clarified that the CCAAT box is important in the switching mechanism from AFP to albumin gene expression. These data are speculated that the genes involving liver cirrhosis might be controlled by C/EBP (Gastroenterology 107 : 499-504,1994).In tissue regeneration, such as l … More iver regeneration, PTHrP is a key cytokine regulated the cell motility and apoptosis (Endocrinology 134 : 1936-1942,1994. Arterioscl Throm Vascul Biol in press 1996). Increased PTHrP expression is also demonstrated to be involved the fibrosis in other organ (J Pathol 175 : 227-236, 1995). Furthermore, we have applied the antisense PTHrP oligonucleotide therapy against PTHrP producing pituitary tumor which is newly established in our laboratory (Cancer Res 56 : 77-86,1996).To further extend the basic research, we have focused on the critical events of liver cirrhosis induced by abnormal expression of cytokines escaping from physiological regeneration or apoptosis, which can eventually induce gene instability and abnomal cell proliferation. The experimental design is in vivo rat animal model which is implanted with PTHrP producing pituitary tumor, previously described. Surprisingly, these rats are developed the liver fibrosis and splenomegaly in 3 months after tumor cell inoculation, and also developed the liver cancer 4 months after tumor implantation.Further studies are planned on clarification of molecular mechanism of cytokine induced liver cirrhosis using This in vivo experimental systems.Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs. Less