Molecular Analysis of PTHrP in Vascular Smooth Muscle Cell.

血管平滑肌细胞中 PTHrP 的分子分析。

• 批准号: 08670256
• 负责人: SEKINE Ichiro
• 金额: $ 1.34万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670256/
• 关键词: VSMC; PTHrP; PTHrP receptor; Endothelial cells; Angiogenesis; Antisense therapy; 内皮細胞; PTH; 動脈硬化; 再狭窄; 石灰化

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

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，有必要研究血管平滑肌细胞（VSMC）或内皮细胞中PTHrP受体介导的信号转导的分子机制。在目前的项目中，我们最初集中分析与血管系统有关的各种疾病中 PTHrP 的表达。接下来，我们研究了PTHrP各种片段在原代培养物中的作用以及转染PTHrP的细胞系的功能。最后，基于PTHrP在VSMC中的病理生理作用，我们尝试开发使用反义PTHrP的潜在治疗方法。再狭窄是球囊血管成形术后的主要问题。因此，我们检查了大鼠模型和人类旋切术样本中 PTHrP 及其受体的表达。 PTHrP 是调节细胞运动的关键细胞因子 (Arterioscl Thromb Vascul Bio1 16 : 565-575 1996)。外源添加 h … 更多 PTHrP (1-34)、hPTHrP (1-141)、hPTHrP (100-114) 和 hPTH (1-34) 对胸苷掺入的作用，α (1) II型co11agen基因表达， 细胞内cAMP和[Ca 2+ ]i水平相似。反义寡核苷酸减少 PTHrP mRNA 翻译，特异性抑制 DNA 合成。这些数据推测，外源添加的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，可能还具有未知的生物学作用(J Endocrinology 150 : 359-368 1996)。为了进一步扩展基础研究，我们将重点放在PTHrP异常表达的癌症关键事件上。过度表达 已在多种与恶性进展相关但无高钙血症的癌症中发现。在大鼠中植入产生PTHrP表达载体的细胞系的体内实验设计已经证明了体内肿瘤进展和细胞周围的钙化基质形成(Endocrine J 43：527-535 1996)。此外，反义 PTHrP 寡核苷酸疗法已被报道为针对产生 PTHrP 的肿瘤的抗血管生成疗法（Cancer Res 56：77-86，1996）。最后，我们感谢这笔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

Yamashita S et al: "Oncogensesis and Molecular Biology on Pituitary Tumors" ed.by Melmed S,Front Horm Res,Basel,karger, 18 (1996)

Yamashita S 等人：“垂体肿瘤的癌发生和分子生物学”，Melmed S 编，Front Horm Res，巴塞尔，karger，18 (1996)

S Ozeki et.al.: "Evidence that implicates the parathyroid hormone-related peptide in vascular stenosis." Arterioscler Thromb Vasc Biol. 16. 565-575 (1996)

S Ozeki 等人：“有证据表明甲状旁腺激素相关肽与血管狭窄有关。”

K. Motomura et. al.: "Autocrine/paracrinerole of parathyroid hormone-relate peptide (1-141) on osteogenic properties in rat ROS cells." Endocrine J. 43. 527-535 (1996)

K.Motomura 等。

A.Gabit et.al.: "Expression of parathyroid hormone-related paptide in human gastric tumours." J Pathol. 182. 174-179 (1997)

A.Gabit 等人：“甲状旁腺激素相关肽在人胃肿瘤中的表达。”

K Motomura et.al.: "Autocrine/paracrinerole of parathyroid hormone-related peptide(1-141)on osteogenic properties in rat ROS cells." Endocrine J. 43. 527-535 (1996)

K Motomura 等人：“甲状旁腺激素相关肽 (1-141) 的自分泌/旁分泌素对大鼠 ROS 细胞成骨特性的影响。”