Molecular Analysis of liver cirrhosis

为了开发日本治疗肝硬变的新疗法，有必要对肝硬变的分子机制进行研究。在目前的项目中，我们主要集中在组织再生的转录调控机制和细胞因子的表达上，因为肝硬变被认为是肝再生中一种受损的形态发生。在前者中，我们利用分化的肝癌细胞系研究了丁酸对甲胎蛋白(AFP)和白蛋白基因表达的影响。在后者中，我们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 box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，与肝硬变相关的基因可能受C/EBP(胃肠病学)控制。在组织再生中，如L…在肝脏再生中，PTHrP是调节细胞运动和凋亡的关键细胞因子(内分泌学134：1936-1942,1994)。动脉血管生物出版社1996年出版)。甲状旁腺激素受体的高表达也被证明与其他器官的纤维化有关(病理杂志175：227-236,1995)。此外，我们还应用反义PTHrP寡核苷酸治疗本实验室新建立的PTHrP产生的垂体瘤(癌症Res56：77-86,1996)。为了进一步扩大基础研究，我们将重点放在由细胞因子异常表达逃避生理性再生或凋亡而导致的肝硬变的关键事件上，最终导致基因不稳定和细胞异常增殖。实验设计为大鼠体内移植甲状旁腺素rP产生肿瘤的动物模型，如上所述。令人惊讶的是，这些大鼠在接种肿瘤细胞后3个月内出现肝纤维化和脾肿大，并在肿瘤移植后4个月发展为肝癌。利用该体内实验系统，计划进一步研究细胞因子诱导的肝硬变的分子机制。最后，我们感谢来自这项资助的支持和我们博士后研究员和工作人员的宝贵贡献。较少

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