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

甲状旁腺激素相关肽（PTHrP）首次从人类肿瘤细胞中分离出来，并被证明与恶性肿瘤体液性高钙血症患者产生高钙血症有关。PTHrP是一种在许多正常组织中也表达的基因的产物，在胎儿和成年动物中已证实PTHrP在胃中的定位。PTH/PTHrP受体的基因表达也在许多组织中得到证实，PTHrP通过PTH/PTHrP受体以自分泌/旁分泌的方式引起生理作用。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。该肽的另一个重要生理作用是细胞增殖和分化在一些组织，如皮肤、软骨、骨和肺。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。本研究采用醋酸性溃疡模型，对标本组织进行免疫组化、原位杂交和Northern blot分析。再生粘膜中PTHrPmRNA的表达在溃疡愈合早期降低。相反，PTHrP受体mRNA相互过表达。在再生早期，EGF和tgf β的表达不涉及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很重要，并且PTHrP参与了后期再生上皮分化的调节。寡感PTHrP明显延缓溃疡愈合。过表达PTHrP可诱导PTHrP受体下调，延缓粘膜再生。进一步研究PTHrP促进胃粘膜再生的分子机制。最后，我们感谢这项资助的支持以及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.