抗血管渗漏肽PEDF（44-mer）和血管生成肽PR39共表达在梗死心肌的作用及相关机制研究

项目名称： 抗血管渗漏肽PEDF（44-mer）和血管生成肽PR39共表达在梗死心肌的作用及相关机制研究

项目编号： No.81501434

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 郝跃文

作者单位： 中国人民解放军第四军医大学

项目金额： 18万元

中文摘要： 传统促血管生成基因治疗多以VEGF为靶点，但忽略了其超强诱导血管渗透性的能力，往往会影响缺血区血管新生的效率。为探讨多顺反子共分泌表达抗血管渗漏肽及血管生成肽治疗心梗的可行性，以及阐明梗死区44-mer抗血管渗漏、PR39抗凋亡及促血管新生作用，本课题通过并接子技术共分泌表达“血管生成总开关”-PR39及PEDF(44-mer)重组腺相关病毒，通过介入技术将其转导至梗死区，在心梗早期启动PR39表达，选择性抑制泛素-蛋白酶体对HIF-1α的降解，来促进血管生成的细胞因子和受体（VEGF等）高表达，既促进血管新生，又抗缺氧应激凋亡，挽救更多“中间地带”缺氧细胞，行SSFP BOLD MR成像评价疗效；在梗死后期过表达44-mer，发挥其抗血管渗漏作用，提高梗死区血管再生效率，并希望阐明44-mer抗血管渗漏作用位点的分子机制研究。本课题将为完善缺血心肌促血管新生的策略，提供可靠的理论基础。

中文关键词： 急性心肌梗死；血管生成；心脏磁共振；PR39；PEDF

英文摘要： Traditional gene therapy research of angiogenesis was fulfilled , but its super ability of inducing vascular permeability was often ignored,therefore,to investigate the feasibility of preventing and treating the myocardial infarction by polycistron secretory express antiangiogenesis leakage peptide and angiogenic peptide,the study will be performed by designing the recombinant AAV which could make secretory expression of the peptide PR39 - an angiogenic master switch and PEDF (44-mer), then was transduced to the coronary artery of insufficiency of hypoxic myocardial muscles by the interventional way. In the early stage of myocardial anoxia and infarction, the expression of PR39 were quickly started,and selectively inhibited the ubiquitin–proteasome-dependent degradation of hypoxia-inducible factor-1α protein (HIF-1α), resulting in the upregulation intra-cellular VEGF, KDR, FLT-1 and FGFR1, PR39 not only promoted angiogenesis,but also protected the survival，saved the intermediate zone in time, to prevent it from the irreversible direction，we will evaluate the effect of myocardial infarction by SSFP BOLD MR. In the late stage of myocardial infarction, AAV cloud play the antiangiogenesis leakage by expressing the 44-mer peptide and improve the angiogenesis efficiency of infarction area, we wish to clarify the molecular mechanism of the antiangiogenesis leakage peptide(44-mer).We expect to provide the new view for the prevention and treatment of cardiac and cerebrovascular disease.

英文关键词： acute myocardial infarction;angiogenesis;cine MRI;PR39;PEDF