Molecular Analysis of Parathyroid Hormone-related Peptide of Regenerative Gastric Mucosa

甲状旁腺激素相关肽(PTHrP)最先从人类肿瘤细胞中分离出来，并被证明是导致恶性体液高钙血症患者高钙血症的原因。PTHrP是一个基因的产物，该基因也在许多正常组织中表达，并且已经在胎儿和成年动物中证明了PTHrP在胃中的定位。PTH/PTHrP受体基因在许多组织中也有表达，PTHrP通过PTH/PTHrP受体以自分泌/旁分泌的方式发挥生理效应。在PTHrP的各种生理作用中，内脏和血管组织的平滑肌松弛是众所周知的。PTHrP的另一个重要生理作用是在皮肤、软骨、骨骼和肺等组织中的细胞增殖和分化。本研究的目的是阐明PTHrP对粘膜再生和细胞周期的分子机制。本研究采用乙酸型溃疡模型，对组织标本进行免疫组织化学、原位杂交和Northern印迹分析。在溃疡愈合早期，再生粘膜中PTHrPmRNA的表达减少。相反，PTHrP受体mRNA相对过表达。在再生的早期阶段，EGF和TGFbeta的表达不参与PTHrP的转录。这些结果表明，PTHrP受体的表达在粘膜再生的早期事件中是重要的，并且PTHrP参与了晚期再生上皮分化的调节。此外，正义寡核苷酸PTHrP明显延缓溃疡愈合。PTHrP过表达导致PTHrP受体下调，延缓胃粘膜再生。进一步的研究计划阐明PTHrP促进胃粘膜再生的分子机制。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。

Parathyroid hormone-related peptide (PTHrP) was first isolated from human tumor cells and was shown to be responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy. PTHrP is the product of a gene that is also expressed in many normal tissues, and the localization of PTHrP in the stomach has been demonstrated in fetal and adult animals. Gene expression of PTH/PTHrP receptor was also demonstrated in many tissues and PTHrP elicits physiological effects through PTH/PTHrP receptor in an autocrine/paracrine fashion. Among the various physiological effects of PTHrP,smooth muscle relaxation in visceral and vascular tissues is well known. Another important physiological role of this peptide is cell proliferation and differentiation in some tissues, such as skin, cartilage, bone, and lung.The purpose of this study is to elucidate the molecular mechanisms of PTHrP on mucosal regeneration and cell cycle. Acetic acid ulcer model was used in this study and the sampling tissues were processed for immunohistochemistry, in situ hybridization, and Northern blot analysis. Expression of PTHrPmRNA was decreased in the regenerative mucosa in the early phase of ulcer healing. In contrast, PTHrP receptor mRNA was overexpressed reciprocally. Expressions of EGF and TGFbeta did not involve transcription of PTHrP in an early stage of regeneration. These results suggest that PTHrP receptor expression is important in the early events of mucosal regeneration and that PTHrP involves regulation of differentiation of the regenerative epithelium in the late phase. Moreover the sense-oligo PTHrP obviously retarded ulcer healing. Overexpression of PTHrP induces PTHrP receptor down regulation and it retards the mucosal regeneration.Further studies are planned on clarification of molecular mechanism of PTHrP on regeneration of the gastric mucosa.Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs.