电压门控性钾通道在糖尿病认知功能障碍中的作用及机制研究

项目名称： 电压门控性钾通道在糖尿病认知功能障碍中的作用及机制研究

项目编号： No.81471031

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈莉娜

作者单位： 西安交通大学

项目金额： 65万元

中文摘要： 60%-70%的糖尿病患者存在轻、中度认知功能障碍，其发病机制尚未明确。电压门控性钾通道（Kv）与认知功能障碍密切相关，但是Kv在糖尿病认知功能障碍中的作用和地位等目前国内外尚未见报道。本课题组前期研究也发现Kv上调可促进认知功能障碍。我们推测Kv参与了糖尿病认知功能障碍的发生，可能通过高血糖、高胰岛素及胰岛素抵抗经由PI3K/Akt通路，使神经元电压门控性钾通道IA和IK电流变化，NMDA电流变化，突触可塑性降低；同时激活caspase，诱导神经细胞凋亡。本项目应用膜片钳技术，结合行为学、分子生物学、免疫组织/细胞化学、激光共聚焦、电镜等技术，在整体、细胞及分子水平上，系统研究葡萄糖、胰岛素水平及胰岛素抵抗对IA和IK的调控及机制，IA和IK功能和表达改变对NMDA受体、细胞内钙、突触功能和结构可塑性等的调控机制，揭示Kv在糖尿病认知功能障碍发生中的作用，为认知障碍的防治提供新靶点。

中文关键词： 电压门控性钾通道；糖尿病；认知障碍；胰岛素抵抗；突触可塑性

英文摘要： Mild and moderate cognitive dysfunction was accounted for 60%-70% in diabetes, however, the mechanism of diabetic cognitive dysfunction was not completely understood. Voltage-gated potassium channel (Kv) is associated with cognitive dysfunction, and our previous study has confirmed it further. We speculate that IA and IK were involved in high glucose, high insulin concentration and insulin resistance through PI3K/Akt pathway in neurons, and then caspase-dependent apoptosis was activated; meanwhile, influenced current of NMDA attenuated synaptic plasticity, which contributed to cognitive dysfunction. This project will adopt patch clamp technique, behavioral science, molecular biology, immunocytochemistry/ immunohistochemistry, confocol, electron microscopy and other techniques in order to clarify the effects of glucose, insulin and insulin resistance on IA and IK, and the mechanism of IA and IK for NMDA receptor, intercellular calcium, synaptic transmission and plasticity on the whole, cell and molecular levels. These findings will demonstrate not only an essential role of Kv in diabetic cognitive dysfunction but also a therapeutic potential target of Kv in cognitive dysfunction treatment.

英文关键词： voltage-gated patassium channels;diabetes;cognitive dysfunction;insulin resistance;synaptic plasticity