受体N-糖链对GLP-1防治糖尿病认知障碍的影响及机制

N-糖链在受体信号转导和疾病过程中起重要作用，探究关键受体N-糖链变化及机制是阐释相关药物作用机理并揭示潜在靶点的关键环节。已有研究表明调控N-糖链合成的N-乙酰氨基葡萄糖转移酶V/III（GnT-V/III）与神经细胞分化、神经退行性疾病发生联系紧密。本课题组前期研究发现并报道了胰高血糖素样肽-1（GLP-1）受体信号系统在防治糖尿病认知障碍中的重要作用，并且已证明N-糖链合成在GLP-1受体介导神经细胞存活中至关重要，但是确切分子机制不明。本项目首先确证N-糖链对GLP-1受体介导信号系统及生物学功能的影响，同时解析受体N-糖链结构特征，并考察糖尿病认知障碍中GLP-1受体N-糖链的特征性变化；进一步，分别建立GnT-V/III基因沉默和过表达神经细胞模型，通过调控糖链合成探讨受体的N-糖链结构改变对GLP-1信号系统及其功能的影响机制。为防治糖尿病认知障碍提供新的研究思路和潜在靶点。

N-glycans play important roles in signal transduction pathways of receptors and procession of diseases, and the N-glycans of important receptor are key for exploring the mechanism of drug action and potential targets. The changes of N-acetylglucosaminyltransferase-V/III (GnT-V/III), which are related to the synthesis of N-glycans, are also involved in the neural differentiation and neurodegenerative diseases. In our previous study, we have found and reported the positive effect of glucagon-like peptide-1 (GLP-1) receptor signal transduction pathways in diabetes-related cognitive dysfunction. We have also found that the synthesis of N-glycans may play a key role in the neuronal survival mediated by GLP-1 receptor, but the mechanism is unclear. In this project, first we will investigate the effect of N-glycans in signal transduction pathways and biological functions of GLP-1 receptor, analyze the structures of N-glycans of GLP-1 receptor, and observe the changes of N-glycans of GLP-1 receptor in diabetes-related cognitive dysfunction; then we will establish models of GnT-V/III gene silencing and over-expression neuronal cell to explore the effect of N-glycans in signal transduction pathways and biological functions of GLP-1 receptor through the regulation of the synthesis of N-glycans. The aim of this project is to provide new ideas about research and new experimental evidence for the potential targets in diabetes-related cognitive dysfunction.