生长分化因子15介导胰高糖素样肽1受体激动剂在2型糖尿病血管内皮功能保护中的作用及机制研究

本项目组前期研究证实，GLP-1受体激动剂（GLP-1RA）具有血管内皮功能保护作用，但其关键机制尚未完全阐明。本项目预实验显示，GLP-1RA治疗可上调2型糖尿病（T2DM）小鼠血浆和内皮细胞中生长分化因子15（GDF15）的水平。然而，GDF15是否介导GLP-1RA的内皮功能保护作用，目前尚未见报道。本项目拟在T2DM小鼠中明确GLP-1RA上调GDF15产生及其主要来源，在多种T2DM小鼠和内皮细胞体外模型中确定GDF15介导GLP-1RA保护内皮功能的作用，明确GLP-1RA调控GDF15的作用是否依赖GLP-1受体途径，筛选和确定调控GDF15的关键转录因子，最终阐明GLP-1RA调控GDF15的分子机制，并在T2DM患者中验证GLP-1RA促进GDF15产生和改善内皮功能的作用，分析GDF15水平与内皮功能改善的相关性。本项目将有助于阐明GLP-1RA保护血管内皮功能的机制。

Our previous study showed that glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) exerts protective properties against endothelial dysfunction. However, the key mechanism remains to be fully elucidated. Our pilot study revealed that the level of growth differentiation factor 15 (GDF15) is elevated in the serum of type 2 diabetic (T2DM) mice and in cultured endothelial cells after treatment with GLP-1RA. At present, whether GDF15 has a role in the protection of GLP-1RA on endothelial function has not yet been reported. In this project, we intend to determine the up-regulating effect of GLP-1RA on GDF15 production in T2DM mice and the main source of this GDF15 elevation; to determine the role of GDF15 in GLP-1RA-mediated endothelial function protection in T2DM mice in vivo and endothelial cells in vitro; to certificate whether the action are mediated via GLP-1 receptor-dependent pathway or not; and to screen and identify a potential key transcript factor for regulating GDF15 expression. These will clarify the molecular mechanisms involved in the regulation of GLP-1RA on GDF15. In addition, we also intend to validate reproducibility of some results including the upregulation of GDF15 production, improvement in endothelial function, and the correlation between the two events in T2DM patients treated with GLP-1RA. Therefore, the project will be helpful to elucidate the regulation of GLP-1RA on GDF15 and its mechanism in the protection of endothelial function.