业已证实，胰高糖素样肽-1（GLP-1）可促进胰岛β细胞新生，但其分子机制尚不明确。本课题组的前期研究发现，GLP-1可促进人胚胎干（hES）细胞定向分化为胰岛素分泌细胞。此外，我们还证实miR-375在hES细胞定向分化为胰岛素分泌细胞过程中发挥重要的调控作用。本项目预实验结果显示，GLP-1可下调分化细胞中miR-375的表达，而miR-375则可下调胰岛转录因子Pax6和Hnf1β的表达。因此，我们推测GLP-1可能通过调控胰岛特异性miRNA和转录因子从而促进β细胞定向分化。本项目拟探讨GLP-1受体及相关信号通路、胰岛分化发育关键miRNA（如miR-375）、胰岛特异性转录因子（如Pax6和Hnf1β）之间的关系，阐明GLP-1调控人胰岛β细胞分化的分子网络。本项目有助于阐明GLP-1药物改善胰岛β细胞功能的新机制，为该类药物在重建胰岛β细胞功能方面的临床应用提供新的理论依据。

It has been demonstrated that glucagon-like peptide-1 (GLP-1) promotes pancreatic β cell neogenesis. However, the mechanism involved is poorly understood. Our previous studies showed that GLP-1 could promote human embryonic stem (hES) cells to differentiate into insulin producing cells. We also confirmed that miR-375 played important regulatory roles during this process. Our preliminary experiments revealed that GLP-1 decreased the expression of miR-375, and that miR-375 downregulated the expression of pancreatic islet-specific transcription factors Pax6 and Hnf1β. Based on the above observations, we speculate that GLP-1 enhances β cell differentiatian and maturation via islet-specific miRNA and transcription factors. In this project, we intend to explore the molecular network of GLP-1 regulating islet β cell differentiation, by investigating the interactions among GLP-1 receptor and its signaling pathways, miRNA involved in islet development and differentiation (such as miR-375), and islet-specific transcription factors (such as Pax6 and Hnf1β). This project will present an novel insights into the roles of GLP-1 agents in regulating human islet β cell conservation, and provide new evidences for the clinical application of GLP-1-based therapies on pancreatic β cell function reconstruction.