Molecular Analysis of PTHrP in Hepatic Regeneration

为阐明甲状旁腺激素相关肽（PTHrP）在肝脏疾病中的病理生理作用，有必要研究PTHrP受体介导的肝实质细胞和非实质细胞（包括内皮细胞）信号转导的分子机制。在本项目中，我们最初集中分析了PTHrP在各种疾病中的表达（J Pathol 182：174-9，J Pathol 187：217-22）。最后，我们尝试利用组织特异性启动子构建PTHrP转基因动物，分析PTHrP在肝再生中的病理生理作用，并研究外源性hPTHrP（1-34）、hPTHrP（1-141）、hPTHrP（1- 1 hPTHrP（100-114）和hPTH（1-34）对胸苷掺入、α（1）Ⅱ型胶原基因表达、细胞内cAMP和[Ca^2^+]i水平的影响相似。反义寡核苷酸 ...更多信息 PTHrP mRNA翻译增加特异性抑制DNA合成。这些数据推测，外源性添加的hPTH和hPTHrP之间没有显着差异，另一方面，细胞内PTHrP除了经典的PTH/PTHrP受体介导的功能外，可能还具有尚不清楚的生物学作用（J Endocrinol 150：359-368）。为了进一步扩大基础研究，我们主要关注PTHrP等细胞因子异常表达所引起的重要事件，这些事件包括PTHrP逃避生理再生或凋亡，最终导致基因不稳定和异常细胞增殖。实验设计为体内大鼠动物模型，皮下植入产生PTHrP的垂体瘤。令人惊讶的是，这些大鼠在肿瘤细胞接种后3个月内发生肝纤维化和脾坏死，并且还显示GST-P阳性灶的数量显著增加。目前正在对PTHrP转基因动物模型进行进一步的研究，该模型已经建立了阳性转基因克隆。最终，我们感谢这笔赠款的支持和我们的后doe研究员和工作人员的宝贵贡献。少

To elucidate the patho-physiological role of parathyroid-hormone-related peptide (PTHrP) in liver disease it is essential to investigate on the molecular mechanism of PTHrP receptor mediated signal transduction in hepatic parenchemal cells and non-parenchemal cells including endothelial cells. In the present projects we have initially concentrated the analysis of PTHrP expression in various disease (J Pathol 182 : 174-9, J Pathol 187 : 217-22). Next, we have studied the effect of various fragments of PTHrP in primary culture and function of the cell lines transfected PTHrP.Finally, we have try to develop the PTHrP transgenic animal using tissue specific promoter of the liver, analyze the pathophysiological role of PTHrP in liver regeneration.The action of exogenously added hPTHrP (1-34), hPTHrP (1-141), hPTHrP (100-114) and hPTH (1-34) on thymidine incorporation, alpha(l) type II collagen gene expression, intracellular cAMP and [Ca^2^+]i level was similar. Antisense oligonucleotides de … More creased PTHrP mRNA translation specifically inhibited DNA synthesis. These data are speculated that there is no significant difference among exogenously added hPTH and hPTHrP, on the other hand intracellular PTHrP may have a yet unknown biological role, in addition to a classical PTH/PTHrP receptor-mediated function (J Endocrinol 150 : 359-368).To further extend the basic research, we have focused on the critical events induced by abnormal expression of cytokines including PTHrP escaping from physiological regeneration or apoptosis, which can eventually induce gene instability and abnormal cell proliferation. The experimental design is in vivo rat animal model, which is subcutaneously implanted with pituitary tumor producing PTHrP.Surprisingly, these rats arc developed the liver fibrosis and splenoniegaly in 3 months after tumor cell inoculation, and also showed the significantly increased number of GST-P positive focus.Further studies are now continuing on PTHrP transgenic animal model, which was already, established positive transgene clone.Finally, we acknowledge a support from this grant and a valuable contribution of our post doe fellows and staffs. Less