GDF11/KLF4/IR通路在阿尔茨海默病发生及其进展中的作用研究

项目名称： GDF11/KLF4/IR通路在阿尔茨海默病发生及其进展中的作用研究

项目编号： No.81500912

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 伊然

作者单位： 哈尔滨医科大学

项目金额： 17.5万元

中文摘要： （限400字）..2014年文献报道，新的血液因子GDF11能够恢复小鼠海马部分区域的活力从而改善其学习和记忆能力，其机制不清。胰岛素信号转导通路异常是AD发生的重要机制之一，胰岛素受体（insulin receptor，IR）是整个胰岛素信号转导通路的起始点和重要靶位。我们已经报道KLF8影响AD的发生，我们近期发现，在侧脑室注射STZ大鼠模型中，GDF11水平降低，IR及KLF4的表达均下调且与GDF11的水平呈正相关；并且生物信息学软件预测显示，IR的启动子区存在KLF4的结合位点；文献证实KLF4可调控IR的表达。据此本研究拟在动物和细胞水平证实，GDF11可通过KLF4调控IR的表达，进而增强胰岛素信号转导通路活性，最终影响AD的发生，并通过临床AD患者的收集进行验证。上述机制如能证实，将为AD的预防及治疗提供新的思路。

中文关键词： 阿尔茨海默病；糖尿病；胰岛素；生长分化因子11；Krüppel；样转录因子4

英文摘要： In 2014, a new blood factor GDF11 was reported to be able to rejuvenate part of hippocampus of mice to improve their learning and memory. However, the mechanism remains unclear. This study will explore the underlying mechanism of GDF11 at vitro and vivo .One of the important mechanisms of AD is abnormal signal transition through the insulin signaling pathway. The insulin receptor (IR) is the starting point and an important target for the entire insulin signaling pathway. The recent research on a mouse model with intracerebroventricular injection of STZ(ICV-STZ) shows that as the expression of GDF11 decreases, the expression of KLF4 and IR are lowered. The expression of IR and KLF4 are positively correlated with the expression of GDF11. In addition, bioinformatics software forecasts that KLF4 binding sites are located at the promoter region of IR, and literature has confirmed that KLF4 can regulate the expression of the IR. This study is aiming at proving the hypothesis that GDF11 can improve the expression of IR by regulating the expression of KLF4, and thus enhance the activity of insulin signaling pathway, and ultimately affect the occurrence of AD. This study will be performed at vitro and vivo , supported by clinical verification research performed among current AD patients. If the above mechanism is proved, it will provide new ideas for the prevention and treatment of AD.

英文关键词： Alzheimer’s disease;diabetes ;insulin;growth differentiation factor 11;Krüppel like factors 4