ZIP9介导的雄激素调节海马神经元树突棘重塑及对学习记忆能力的影响

Decreased androgen levels may be a risk factor for Alzheimer's disease (AD) in elderly men. Androgen is related to the regulation of synaptic plasticity, but whether the regulation is the classical genomic effect mediated by intracellular receptor (iAR) or the non-genomic effect mediated by membrane receptor (mAR) is the bottleneck in the study of androgen effect, which needs to be further studied. Our previous work found that there was mAR in the hippocampal neuron membrane, androgen affected dendritic spine density and synaptic protein through mAR-mediated non-genomic effects. On the basis of previous studies, this project will make a breakthrough study on the origin of androgen non-genomic effects with ZIP9/Gnalpha11 as the breakthrough point. Then, the mechanism of dendritic local synaptic protein PSD95 mRNA translation was used to investigate whether ERK activates translation initiation and whether the translation initiation factors eIF4E and S6 are phosphorylated in a highly ERK-dependent manner, thus participating in ZIP9/Gnalpha11-mediated androgen non-regulation. Genomic effects regulate the translation process of PSD95 mRNA. On this basis, we discussed the effect of ZIP9 mediated androgen on learning and cognitive function.

雄激素水平降低可能是老年男性患阿尔茨海默病（AD）的危险因素。雄激素与突触可塑性调节具有相关性，但调节作用是胞内受体（iAR）介导的经典的基因组效应，还是膜受体（mAR）介导的非基因组效应，这一问题是我们研究雄激素效应的瓶颈，亟需加强研究。我们前期工作发现，海马神经元细胞膜存在mAR，雄激素通过mAR介导的非基因组效应影响树突棘密度和突触蛋白。本项目将在前期研究基础上，以ZIP9/Gnα11为切入点，进行雄激素非基因组效应始作之源的突破性研究。再以树突局部突触蛋白PSD95 mRNA翻译机制为契合点，从树突局部mRNA合成突触蛋白参与树突棘重塑着手，研究ERK是否激活翻译起始以及翻译起始因子eIF4E和S6是否以一种高度ERK依赖的形式被磷酸化，从而参与ZIP9/Gnα11介导的雄激素非基因组效应调控PSD95 mRNA翻译过程。在此基础上探讨ZIP9介导雄激素对学习认知功能的影响。

雄激素水平降低可能是老年男性患阿尔茨海默病（AD）的危险因素。雄激素与突触可塑性调节具有相关性，但调节作用是胞内受体（iAR）介导的经典的基因组效应，还是膜受体（mAR）介导的非基因组效应，这一问题是我们研究雄激素效应的瓶颈，亟需加强研究。我们前期工作发现，海马神经元细胞膜存在mAR，雄激素通过mAR介导的非基因组效应影响树突棘密度和突触蛋白。本项目开展了关于海马神经元ZIP9/Gnα11的研究是对雄激素非基因组效应始作之源的突破性研究。以ZIP9为切入点、以树突局部突触蛋白PSD95合成影响树突棘重塑为契合点，揭示ZIP9介导的雄激素调节海马神经元树突棘重塑的机制。利用iAR缺陷的Tfm小鼠，研究ZIP9介导的雄激素对学习记忆能力的影响。本项目从分子、细胞、整体多水平系统研究ZIP9介导的雄激素调节海马神经元树突棘重塑的机制及对学习记忆能力的影响，阐明雄激素非基因组效应对突触可塑性的调节并为防治雄激素相关的AD提供药物治疗靶点新策略。