雄激素非基因组效应对海马神经元树突局部PSD95mRNA翻译的调控及FMRP机制研究

Hippocampus retains some degree of androgen-regulated neuroplasticity had been identified. But there has little studies demonstrated that the effects of androgen are gennomic action or non-genomic action. We had indentified the presence and specificity of membrane androgen binding sites and found androgen induced a rapid increase in the density of dendritic spines and synaptic proteins. The non-genomic effects of androgen can affect synaptic plasticity of hippocampal neurons. However, the mechanisms remains undefined. Based on the previous studies, we combine the new theory of local synaptic protein synthesis in dendrites and androgen non-genomic effects, choosing PSD95, which is one of the most important postsynaptic scaffolding protein, as the breakthrough point: ① Determining the effect of androgen non-genomic effects on the generation of postsynaptic protein PSD95 in hippocampal neurons; ② Identifying androgen non-genomic effects on the regulation of dendritic PSD95 mRNA translation of synaptic proteins in hippocampal neurons; ③ Exploring the effect of FMRP on the activity of PSD95 mRNA translation in the dendrites of hippocampal neurons and the effect of androgen on the local PSD95 synthesis in the dendrites by FMRP and miRNA. This project not only provide evidence for androgen neuroprotective mechanisms of synaptic plasticity, but also provide new ideas for the pathogenesis of AD among older men.

雄激素与突触可塑性调节具有相关性已被证实，但少有对此作用方式是基因组效应还是非基因组效应的明确报道。我们此前证实了海马神经元细胞膜上存在mAR，近期又观察到雄激素主要通过非基因组效应影响了树突棘密度和突触蛋白，但雄激素非基因组效应的机制尚不未明确。本项目将突触蛋白在树突局部合成理论和雄激素非基因组效应调控突触可塑性巧妙契合，以PSD95这一重要的突触后支架蛋白为突破点进行研究：①明确雄激素非基因组效应影响海马神经元突触后支架蛋白PSD95的生成；②确证雄激素非基因组效应调控海马神经元树突局部PSD95mRNA翻译合成突触蛋白；③研究FMRP对海马神经元树突局部PSD95mRNA翻译活动的影响并基于FMRP与miRNA关联理论进行雄激素影响树突局部PSD95合成的探讨。本项目不仅为揭示雄激素神经保护机制提供突触可塑性方面的依据，也为进一步认识老年男性AD的发病机制提供新的思路和理论依据。

雄激素与突触可塑性调节具有相关性已被证实，但国内外少有对此作用方式是基因组途径还是非基因组途径的明确报道。本项目多角度证实海马神经元细胞膜上存在mAR，为雄激素调节突触可塑性机制研究指明方向。突触蛋白在树突局部短时程的可塑性变化，与雄激素快速的突触后可塑性非基因组效应仅是事件上的偶然，还是两者有不为所知的密切关系？本项目将就这一科学问题进行探秘解答，以PSD95这一重要的树突棘支架蛋白为突破点，明确雄激素对其的影响是不依赖于基因转录的非基因组效应，且通过调节转录后PSD95在树突局部翻译合成来实现。FMRP在雄激素对PSD95基因转录后的树突局部翻译的激活性作用中是否起到了关键性作用，目前国内外还没有研究报道，亦无基于FMRP与miRNA关联理论而进行的雄激素影响树突局部PSD95合成的探讨。本项目就此进行探讨，明确FMRP作为mRNA结合蛋白在雄激素对PSD95树突局部翻译的激活性作用中起到了关键性作用。本项目不仅为揭示雄激素神经保护机制提供突触可塑性方面的依据，也为进一步认识老年男性AD的发病机制提供新的思路和理论依据。