TRPC1介导的钙信号在电磁辐射影响胚胎神经发生中的作用及机制

Growing evidences confirm that electromagnetic fields (EMF) injury neurodevelopment. Embryonic neurogenesis, which is based on embryonic neural stem cells (eNSCs), is the key process of neurodevelopment. Previous studies suggest that the bioeffects of EMF were largely mediated by influcing calcium signaling. However, eNSCs is non-exitable cells and the effects of EMF on calcium signaling in non-exitable cells remains unclear. TRPC1 is one of the key calcium channel which plays an important role in regulating embryonic neurogenesis. Our previous studies found that EMF exposure up-regulated TRPC1 gene and protein expression in eNSCs, which evaluated calcium influx and inhibited eNSC proliferation. We also found that Dll1, one of the downstream factors of calcium signaling, was downregulated after EMF exposure. Based on this, we hypothesis that EMF exposure evaluated calcium influx through TRPC1, which activated Dll1/Notch1 signaling, and influenced embryonic neurogenesis. We plan to study: (1) The effects of EMF exposure on embryonic neurogenesis, and its time- and dose-dependent effects. (2) The changes of the expression and function of TRPC1 and the calcium signaling mediated by TRPC1 after EMF exposure, and the role of TRPC1-mediated calcium signaling in EMF influencing embryonic neurogenesis. (3) The protective effects of regulating TRPC1-mediated calcium signaling on embryonic neurogenesis after EMF exposure. This study could explore new cellular and molecular mechanisms of EMF on brain development, and provide new targets for protection EMF injury.

电磁辐射（EMF）影响神经发育，而基于胚胎神经干细胞（eNSCs）的神经发生是神经发育的核心问题。调控钙信号是EMF主要效应机制之一，但EMF对eNSCs这类非兴奋性细胞钙信号的影响及机制不明。TRPC1是调控胚胎神经发生的关键钙通道，我们前期研究发现，EMF可上调eNSCs内TRPC1表达，促进Ca2＋内流，抑制eNSCs增殖。基于以上结果，以及我们在上一项目中发现EMF上调钙信号下游分子Dll1表达的现象，我们假设：EMF通过TRPC1介导的钙信号影响Dll1/Notch1信号活性，从而损伤胚胎神经发生。项目主要研究：（1）EMF影响胚胎神经发生的时效量效关系；（2）TRPC1介导的钙信号在EMF影响胚胎神经发生中的作用及机制；（3）调控TRPC1介导的钙信号对EMF损伤胚胎神经发生的改善作用。本项目有望揭示EMF影响神经发育新的细胞靶点及分子机制，为EMF损伤防治提供新思路。

电磁辐射影响神经发育，而基于胚胎神经干细胞（eNSCs）的神经发生是神经发育的核心问题。本项目重点研究了电磁辐射对eNSCs增殖、分化的影响及其相应的分子机制，研究比较了工频（50 Hz）及射频（1800 MHz）对eNSCs作用的异同点，同时探讨了电磁辐射作用于eNSCs的直接间接机制。研究发现，SAR值4 W/kg及以下射频（1800 MHz）电磁辐射对eNSCs凋亡、增殖以及分化神经元及胶质细胞比例无明显影响，但4 W/kg辐射显著损伤分化新生神经元突出生长，其机制与电磁辐射改变bHLH家族基因表达有关。工频（50 Hz）电磁辐射1 mT能够明显促进eNSCs向神经元分化，并且促进分化神经元的突出生长，其机制为电磁辐射通过调控瞬时受体电位通道1（TRPC1）介导的钙信号功能，进一步影响bHLH家族基因表达。我们还发现，电磁辐射可通过影响甲状腺激素的分泌，进一步影响中脑eNSCs的增殖分化。甲状腺激素对中脑eNSCs向多巴胺神经元的分化成熟起关键作用，其机制为甲状腺激素调控TRPC1介导的钙信号功能，进一步影响决定多巴胺神经元分化的关键转录因子OTX2、NURR1及NGN2的表达。本项目研究揭示了工频及射频电磁辐射对eNSCs增殖分化的具体作用特点及差异，以及TRPC1介导的钙信号在其中发挥的调控作用，并且探讨了电磁辐射通过甲状腺激素而间接作用于脑发育的具体作用及分子机制。相关研究结果对全面了解电磁辐射对脑发育的影响及机制提供了实验依据。