Molecular Analysis of PTHrP in Vascular Smooth Muscle Cell.

为了阐明甲状旁腺激素相关肽(PTHrP)在血管系统中的病理生理作用，有必要研究PTHrP受体介导的血管平滑肌细胞(VSMC)或内皮细胞信号转导的分子机制。在目前的项目中，我们初步集中分析了PTHrP在各种涉及血管系统的疾病中的表达。接下来，我们研究了PTHrP的不同片段在原代培养中的作用以及转导PTHrP的细胞系的功能。最后，基于PTHrP在VSMC中的病理生理作用，我们试图开发反义PTHrP治疗VSMC的方法。因此，我们检测了PTHrP及其受体在大鼠模型和人类动脉粥样硬化切除标本中的表达。甲状旁腺素受体是调节细胞运动的关键细胞因子(动脉血栓血管生物1 16：5 65-5 75 1996)。外源性添加h…的作用更多的PTHrP(1-34)、hPTHrP(1-141)、hPTHrP(100-114)和hPTH(1-34)对胸腺嘧啶核苷掺入、α(1)II型胶原基因表达、细胞内cAMP和[Ca^&lt；2&gt；]i水平影响相似。反义寡核苷酸减少PTHrP mRNA的翻译，特异性地抑制DNA合成。这些数据推测，外源添加的hPTH和hPTHrP之间没有显著差异，另一方面，细胞内的PTHrP除了具有经典的PTH/PTHrP受体介导的功能外，还可能具有未知的生物学作用(J Endocinkology 150：359-368 1996)。为了进一步扩大基础研究，我们将重点放在通过PTHrP的异常表达而导致的癌症的关键事件上。将PTHrP表达载体植入大鼠体内的实验设计表明，体内肿瘤进展和细胞周围钙化的基质形成(Endocine J 43：527-1996)。此外，反义PTHrP寡核苷酸疗法已被报道为一种针对PTHrP产生的肿瘤的抗血管生成疗法(癌症资源56：77-86,1996)。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 elucidate the patho-physiological role of parathyroid-hormone-related peptide (PTHrP) in vascular system, it is essential to investigate on the molecular mechanism of PTHrP receptor mediated signal transductionin in vascular smooth muscle cells (VSMC) or endotherial cells. In the present projects, we have initially concentrated the analysis of PTHrP expression in various disease involeved with vascular systems. 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 develope the potentially therapeutic approach using antisense PTHrP,based on the pathophysiological role of PTHrP in VSMC.The restenosis is a major problem after baloon angioplasty. Thus, we examined the expression of PTHrP and its receptor in both rat model and human atherectomy samples. PTHrP is a key cytokine to regulate the cell motility (Arterioscl Thromb Vascul Bio1 16 : 565-575 1996).The action of exogenously added h … More PTHrP (1-34), hPTHrP (1-141), hPTHrP (100-114) and hPTH (1-34) on thymidine incorporation, alpha (1) type II co11agen gene expression, intracellular cAMP and [Ca^<2+>]i level was similar. Antisense oligonucleotides decreased 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 Endocrinology 150 : 359-368 1996).To further extend the basic research, we have focused on the critical events of cancer by abnormal expression of PTHrP.PTHrP overexpression have been found in various cancers associated with malignant progression without hypercalcemia. The in vivo experimental design which was implanted with PTHrP expresion vector producing cell lines in rat have demanstrated in vivo tumor progression and caltified matrix formation around the cells (Endocrine J 43 : 527-535 1996). Furthermore, the antisense PTHrP oligo-nucleotide therapy have been reported as a anti-angiogenic therapy against PTHrP producing tumor (Cancer Res 56 : 77-86, 1996).Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs. Less