抗心肌纤维化新靶点--Apelin相关受体APJ

预防和逆转心肌纤维化是目前心血管疾病的主要治疗目标，但心肌纤维化发生机制错综复杂阻碍新靶点的发现和新药物的开发。APJ,即Apelin相关受体，与其配体脂肪因子Apelin结合后参与免疫炎症、水盐和能量代谢等生理过程。前期研究首次发现心肌纤维化动物和细胞模型中APJ表达均降低，提示APJ可能参与心肌纤维化病理进程。本项目拟采用不同动物、细胞模型和慢病毒载体系统深入研究APJ对心肌纤维化的调控作用及机制，确证APJ是抗心肌纤维化新靶点。利用同源膜建方法构建APJ三维结构，通过高通量分子对接技术结合纤维化相关实验筛选以APJ为靶点的药物，确定侯选药物为白三烯受体拮抗剂扎鲁司特，并探讨其抗心肌纤维化作用及机制。本项目对APJ功能及作用机制的解析将拓展对心肌纤维化这一重大生命科学问题的认知，并为以扎鲁司特分子结构和作用模式为基础研发新型抗纤维化药物提供研究策略。

Preventing and reversing myocardial fibrosis is the main therapeutic target of cardiovascular disease, but the mechanism of myocardial fibrosis is complicated and hinders the discovery of new targets and drug development. APJ, Apelin related receptor, is involved in the physiological processes of immune inflammation, water salt and energy metabolism after combining with the ligand-- fat factor Apelin. In the previous study, we firstly found that the expression of APJ in mice model and in cardiac fibroblast induced by Ang II were both decreased, which suggested that APJ could play a role in myocardial fibrosis process. This project is to investigate the regulation mechanism of APJ in myocardial fibrosis by using different animal model, cardiac myoblast and lentiviral vector system and confirm that APJ is a new target of anti-myocardial fibrosis. Using the method of homologous membrane built the three-dimensional structure of APJ and high-throughput molecular docking technology forecast combining with the screening experiments of anti-fibrosis drugs, we find the target drug--leukotriene receptor antagonist zafirlukast. We will clarify its mechanism of anti-myocardial fibrosis. The project will find the function and mechanism of APJ which will expand the recognization of myocardial fibrosis and find new targets for myocardial fibrosis. The project will provide the new fibrosis drugs research strategies through the molecular structure and function recognization of zafirlukast and strengthen the basis of research and development of antifibrosis drug.