Molecular Analysis of liver cirrhosis

肝硬化的分子分析

• 批准号: 06807051
• 负责人: OHTSURU Akira
• 金额: $ 1.28万
• 依托单位: Nagasaki Univarsity
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06807051/
• 关键词: liver cirrhosis; liver regeneration; PTHrP; PTHrP receptor; AFP; albumin

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

为了开发日本肝硬化的新疗法，有必要研究肝硬化的分子机制。在目前的项目中，我们主要关注组织再生的转录控制机制和细胞因子表达，因为肝硬化被认为​​是肝脏再生中的一种形态发生失调。在前者中，我们使用分化的肝癌细胞系研究了丁酸盐对甲胎蛋白（AFP）和白蛋白基因表达的影响。随后，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盒在AFP到白蛋白基因表达的转换机制中发挥着重要作用。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)。在组织再生中，例如肝脏再生，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 出版，1996 年）。增加的PTHrP表达也被证明涉及其他器官的纤维化(J Pathol 175：227-236，1995)。此外，我们还应用了本实验室新建立的针对产生PTHrP的垂体瘤的反义PTHrP寡核苷酸疗法（Cancer Res 56：77-86，1996）。为了进一步扩展基础研究，我们重点关注因生理再生或细胞凋亡逃逸的细胞因子的异常表达而诱发的肝硬化的关键事件，这可能会导致肝硬化的发生。 最终导致基因不稳定和异常细胞增殖。实验设计是体内植入大鼠动物模型，该模型植入先前描述的产生垂体肿瘤的PTHrP。令人惊讶的是，这些大鼠在肿瘤细胞接种后 3 个月内出现肝纤维化和脾肿大，并在肿瘤植入后 4 个月内出现肝癌。计划进一步研究使用该体内实验系统阐明细胞因子诱导肝硬化的分子机制。最后，我们感谢这项资助的支持以及我们的博士后研究员和工作人员的宝贵贡献。较少的

项目成果

S.Ozeki, et al.: "Evidence implicating parathyroid hormone-related peptide in vascular stenosis : Increased gene expression observed in the intima of injured rat carotid arteries and human restenotic coronary lesions." Arterioscler Thromb Vascul Biol. (in

S.Ozeki 等人：“表明甲状旁腺激素相关肽与血管狭窄有关的证据：在受伤的大鼠颈动脉和人类再狭窄冠状动脉病变的内膜中观察到基因表达增加。”

Hamasaki K, et al.: "Changes in the prevalence of HBeAg-negative mutant hepatitis B virus during the course of chronic hepatitis B." Hepatology. 20. 8-14 (1994)

Hamasaki K 等人：“慢性乙型肝炎病程中 HBeAg 阴性突变型乙型肝炎病毒流行率的变化。”

Nakayama T,et al.: "Coronary atherosclerotic smooth muscle cells overexpress human parathyroid hormone-related peptides" Biochem Biophys Res Communm. 200. 1028-1035 (1994)

Nakayama T 等人：“冠状动脉粥样硬化平滑肌细胞过度表达人甲状旁腺激素相关肽”Biochem Biophys Res Communm。

Tsutsumi T, et al.: "Reciprocal regulation of α-fetoprotein and albumin gene expression by butyrate in human hepatoma cells." Gastroenterology. 107. 499-504 (1994)

Tsutsumi T 等人：“人肝癌细胞中丁酸盐对甲胎蛋白和白蛋白基因表达的相互调节。”胃肠病学。

T,Tsutsumi, et al.: "Reciprocal regulation of alpha-fetoprotein and albumin gene expression by butyrate in human hepatoma cells.19GC01 : Gastroenterology" 107. 499-504 (1994)

T,Tsutsumi 等人：“人肝癌细胞中丁酸盐对甲胎蛋白和白蛋白基因表达的相互调节。19GC01：胃肠病学”107. 499-504 (1994)