Tβ4稳定HIF-1α功能的信号通路及其促进大鼠心梗后血管新生的作用机制研究

项目名称： Tβ4稳定HIF-1α功能的信号通路及其促进大鼠心梗后血管新生的作用机制研究

项目编号： No.91539111

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 杨进福

作者单位： 中南大学

项目金额： 80万元

中文摘要： 目前冠心病的各种治疗方法均不十分理想。我们前期研究证实血管内皮生长因子（VEGF）转染骨髓间充质干细胞（MSCs）移植入心梗区可促进血管新生和改善心功能，为避免单一生长因子作用生成的血管存在不稳定和易渗漏问题，进一步将缺氧诱导因子（HIF）转染MSCs，通过促进HIF表达来调节下游多种生长因子共同作用以生成成熟稳定的新生血管，然而我们同时发现HIF表达存在时效较短的问题。胸腺素β4（Tβ4）是强有力的促进冠脉生成和稳定的刺激因子，有研究表明Tβ4可通过稳定HIF-1α来影响VEGF的表达而促进血管新生，然而其具体机制不明。本课题拟通过外源性Tβ4干预MSCs，观察其对HIF-1α表达的调控作用并探讨可能的机制，同时将转染Tβ4的MSCs移植入大鼠心梗区，观察体内其与HIF-1α和VEGF之间的关系，以及对心梗区血管新生的作用和心梗后心功能的影响。为Tβ4治疗冠心病提供理论依据和实验基础。

中文关键词： 胸腺素β4；缺氧诱导因子-1α；信号通路；基因治疗；冠心病

英文摘要： Coronary heart disease (CHD) has become one of the most serious diseases to jeopardize human health in recent years in our country. But present traditional treatments for CHD such as medicine, interventional therapy or surgery have some disadvantages. Our previous experiment has confirmed that transplantation of bone marrow stromal cells (MSCs) transferred with vascular endothelial growth factor (VEGF) into myocardial infarction area can promote angiogenesis and improve cardiac function. Because the new blood vessels induced by a single growth factor have the problem of instability and leakage, we then tried to transferred Hypoxia-inducible factor (HIF) gene into MSCs to adjust its downstream growth factors acting together to generate mature and stable neovascularization by promoting the expression of HIF. However, we also found the expression of HIF was time limited. Thymosin β4 (Tβ4) is a powerful stimulating factor for coronary vessel generation and stability. It was showed that Tβ4 can improve the expression of VEGF and promote angiogenesis by stabilizing HIF-1α, but its exact mechanism is unclear. So here we plan to use exogenous Tβ4 intervening MSCs to observe its effect to HIF-1α and explore its possible mechanism. Simultaneously, we transplant MSCs transferred with Tβ4 gene into rat myocardial infarction area to observe the relation between Tβ4, HIF-1α and VEGF, and examine its effect to angiogenesis in infarcted area and cardiac function after myocardial infarction. This may be helpful for Tβ4 treatment of coronary heart disease by providing a theory basis and experimental foundation.

英文关键词： Thymosin β4;Hypoxia inducible factor-1α;Signal pathway;Gene Therapy;Coronary Heart Disease