Mipu1促血管新生的机制研究：对VEGF-VASH1/SVBP负反馈通路的转录调节

项目名称： Mipu1促血管新生的机制研究：对VEGF-VASH1/SVBP负反馈通路的转录调节

项目编号： No.81470408

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王慷慨

作者单位： 中南大学

项目金额： 73万元

中文摘要： Mipu1是本室从缺血预适应心肌中克隆的新基因，证实其具有促心肌细胞生长和抗心肌细胞凋亡作用，但其是否调节血管新生，尚无报道。VEGF-VASH1/SVBP是唯一的内皮源性血管新生负反馈调节通路。申请者近期发现：①Mipu1促进内皮细胞增殖和抑制其凋亡、促进管型形成；②Mipu1抑制VASH1和SVBP表达与分泌、促进VEGF表达；③VEGF、VASH1和SVBP启动子区含多个Mipu1结合序列。因此，我们假设Mipu1可能在转录水平通过多靶点调节VEGF-VASH1/SVBP负反馈通路，发挥促血管新生作用。本项目以VEGF-VASH1/SVBP通路中关键分子的转录调节为切入点，从整体、细胞和分子水平，采用ChIP、EMSA和免疫沉淀等方法，深入探讨Mipu1促血管新生的分子机制。期望进一步拓展新基因Mipu1在心肌保护领域的生物学功能，并为血管新生反馈调节机制研究提供新的线索和实验依据。

中文关键词： 血管新生；内皮细胞；Mipu1；VEGF-VASH1/SVBP信号通路；缺氧应激

英文摘要： Novel gene Mipu1 (myocardial ischemic preconditioning up-regulated protein 1), was cloned from rat myocardium insulted with ischemic preconditioning. We recently have verified that Mipu1 serves as an endogenous gene characterized with anti-apoptosis and promoting cell growth in cardiomyocytes. However, it is not clear whether Mipu1 contributes to the regulation of angiogenesis process in heart. VEGF-VASH1/SVBP, the only endothelium-derived negative feedback pathway for regulating angiogenesis. VASH1 (vasohibin 1) plays inhibitory effect on angiogenesis. Its secretion from endothelial cell depends on SVBP (small vasohibin binding protein) and its expression is induced by VEGF while suppressed by hypoxia stress.In previous works, we found that Mipu1 can promote HUVEC proliferation and inhibit hydrogen peroxide-induced apoptosis; Mipu1 promoted hypoxia-mediated HUVEC migration and tube formation; it also increase the expression of VEGF and reduce the expression and secretion of VASH1 and SVBP. And found that the promoter regions of VEGF, VASH1 and SVBP contain several Mipu1 binding core sequence. Therefore, we assume that Mipu1 would promote positively hypoxia-mediated angiogenesis process by tanscriptional regulating the negative feedback pathway VEGF-VASH1/SVBP at multiple sites. This project is designed to clarify the molecular mechanism by which Mipu1 regulate positively hypoxia-mediated angiogenesis process via regulating VEGF-VASH1/SVBP negative feedback pathway of angiogenesis, through a series of experiments on the key biological events (apoptosis, proliferation, migration and tube formation) of angiogenesis process by using ChIP, EMSA and immunoprecipitation at animal，celullar and molecular models. We expect to further expand the biological function of novel gene Mipu1 in the research field of myocardial protection and provide new clues and experimental basis for the study of feedback regulation mechanism of angiogenesis.

英文关键词： angiogenesis;endothelial cells;Mipu1;VEGF-VASH1/SVBP pathway;hypoxia