细胞骨架蛋白Erbin通过调节血管新生促进动脉粥样硬化发生发展

Investigating the mechanisms of the development of atherosclerosis has become one of the most urgent topics in the field of cardiovascular research. Recent studies have shown that as a cytoskeleton protein, Erbin has been involved in the regulation of neovascularization, which has been seen as one of the most important mechanism regulating the development of AS. Recently, we observed that Erbin was mainly expressed in endothelial cells in human coronary artery plaque, and promoted the migration and tube formation of endothelial cells, suggesting that Erbin may be involved in the development of AS by regulating neovascularization. The research group intends to firstly observe the correlation between Erbin expression level and intra-plaque neovascularization and AS through the collected human coronary artery; through construction of Erbin interference and over-expression lentiviral and transfection to ApoE-/- mice, and cultivation of Erbin-/-ApoE-/- double knockout mice, we can clarify the influence of Erbin on neovascularization and AS in animal level; then through in vitro studies, we can illuminate the effects of Erbin on endothelial cell proliferation, apoptosis, migration and tube formation; finally through detection of multiple signaling pathways we can illustrate the specific molecular mechanism. The results can not only reveal the effect of Erbin on the occurrence and development of AS, but also provide a new intervention target for prevention and control of atherosclerotic disease.

动脉粥样硬化（Atherosclerosis，AS）发生发展的机制是心血管研究领域最重要的课题之一。近期研究发现Erbin作为细胞骨架蛋白，参与调控血管新生，而血管新生是影响AS发生发展的重要机制。我们前期研究观察到Erbin在人冠状动脉斑块中主要表达于内皮细胞，并促进内皮细胞迁移和成管，提示Erbin可能通过调控血管新生参与AS的发生发展。课题组收集人冠脉标本观察Erbin表达水平与斑块内新生血管及AS的相关性；通过构建Erbin干扰及高表达慢病毒转染ApoE-/-小鼠，并培育Erbin-/-ApoE-/-双敲小鼠，明确其在整体动物水平对血管新生及AS影响；继而通过体外实验明确Erbin对内皮细胞增殖、凋亡、迁移、成管等影响；最后通过检测多条信号通路明确其发挥生物学作用的分子生物学机制。所得结果可以揭示Erbin对AS发生发展的影响，更可为AS的防治提供新的干预靶点和实验依据。

动脉粥样硬化（Atherosclerosis，AS）发生发展的机制是心血管研究领域最重要的课题之一。课题组前期研究观察到Erbin在人冠状动脉斑块中主要表达于内皮细胞，并促进内皮细胞迁移和成管，提示Erbin可能通过调控血管新生参与AS的发生发展。本研究在既往研究的基础上，完成了Erbin基因敲除小鼠的构建和繁殖，并花费大量时间和人力合成了Erbin-Tek-creERT2-APOE双基因敲除小鼠，用以研究动脉粥样硬化的发生发展及斑块稳定性，为实验的顺利进行奠定了坚实的基础。实验结果表明Erbin基因不仅促进血管新生，还可以心梗后改善心功能，减轻心脏重构。在整体动物水平对血管新生有促进作用。体外实验表明，Erbin促进人脐静脉内皮细胞（HUVECs）迁移、成管，不影响增殖与凋亡。Erbin基因敲除组小鼠结扎冠脉前降支后生存率下降，心脏射血分数下降，心肌纤维化程度加重，梗死面积增大。体外实验结果显示，Erbin干扰后，小鼠心肌细胞凋亡增加，胶原生成增加。研究证实，通过Smad 1/5通路在内皮细胞迁移和小管形成中起关键作用。本研究的组织实施阐明 Erbin 如何影响动脉粥样硬化的发生发展，为动脉粥样硬化机制的研究开辟新的领域，为动脉粥样硬化的防治提供新的靶点，为新药物的开发提供新的途径。在本项目的资助下，项目负责人以通讯作者或第一作者发表原著研究SCI论文6篇，总计IF18.41。