miR-194对Neuritin的靶向调控及其在阿尔兹海默病中的作用及机制研究

The study showed that the expression of Neuritin (NRN1) was decreased in nerve injury (including AD), and NRN1 protein treatment have obvious repairment. However, the molecular mechanism about NRN1 reduction in AD was unclear. We hypothesized that some miRNAs in AD maybe downregulated NRN1 expression to affect the generation and development of AD. We have screened candidate miRNAs that maybe targeted NRN1 in AD, and preliminary results showed the correlation between miRNAs and NRN1 in AD and the inhibiton of miR-194 on NRN1. This study will make clear the association of the level of miR-194 or NRN1 and the ability of learning and memory in AD transgenic mice. And then we will investigate the role and mechanism of miR-194 in the generation and development of AD by up-regulation of miR-194 and down-regulation of NRN1. Finally, we will treated AD mice or AD cell model with miR - 194 specific inhibitors and NRN1 recombinant protein to observe the improvement in AD pathological feature, the synaptic plasticity and mice behavior. We will give an aggregate analysis about the feasibility of miR - 194 and NRN1 as the diagnostic and therapeutic targets in AD, which will provide the foundation for further clinical application research.

研究发现在神经损伤时（包括AD）Neuritin(NRN1)表达降低，而给予NRN1蛋白有明显修复作用。然而，关于AD中NRN1表达降低的分子机制尚不明确。我们推测：AD中某些miRNA可能下调NRN1表达而影响AD的发生发展。我们前期筛选了AD中可能靶向NRN1的候选miRNA，基本明确在AD中它们与NRN1的相关性及miR-194对NRN1的抑制作用。本研究拟首先明确miR-194和NRN1的表达与转基因AD鼠学习记忆障碍的相关性；进一步通过上调miR-194和下调NRN1，探讨miR-194在AD发生发展中作用及机制；最后给予miR-194抑制剂及NRN1重组蛋白，观察对AD鼠及细胞的AD病理特征、突触可塑性及行为学的改善作用，明确miR-194抑制剂和NRN1蛋白在AD治疗中的有效性，综合分析miR-194和NRN1作为AD诊断和治疗靶点的可行性，为进一步临床应用研究提供实验依据。