Arc/Arg3.1调控谷氨酸受体表达与功能在创伤性脑损伤中的作用及机制研究

Traumatic brain injury (TBI) has high incidence and morbidity, and is the most serious kind of trauma. Previous studies indicated that glutamate receptor-mediated excitotoxicity is the main reason for the secondary brain injury after TBI, but the underlying molecular mechanism is still unclear and drug treatment in clinical practice is limited. Arc/Arg3.1 is a neuron-specific postsynaptic protein that is involved in synaptic signal transduction and play important roles in learning and memory. Our previous data showed that neuronal injury increased the expression of Arc/Arg3.1 and knockdown of Arc/Arg3.1 significantly increased the expression of mGluRs in cellular membrane surface with aggravated neuronal injury. Together with recent studies, these results suggest that Arc/Arg3.1 might influence TBI-induced excitotoxicity through regulating the expression and function of glutamate receptors. On the basis of previous studies, the expression and role of Arc/Arg3.1 in TBI, the molecular mechanisms underlying Arc/Arg3.1-induced regulation on glutamate receptors function, as well as the possible interaction between Arc/Arg3.1 and other postsynaptic proteins will be studied by using lentivirus-mediated overexpression and downregulation technology. This project is critical for the significance of deeply understanding the mechanism of secondary brain injury after TBI and extending the value of Arc/Arg3.1 in clinical application.

创伤性脑损伤（TBI）有较高的发生率和死亡率，是创伤中最严重的一类。研究表明，谷氨酸受体介导的兴奋性毒性是TBI后继发性脑损伤的重要原因，但其分子机制尚未阐明，且缺乏有效的药物干预措施。Arc/Arg3.1是一种神经元特异性突触后蛋白，介导突触间信号转导，参与学习和记忆等生理过程。我们研究发现，Arc/Arg3.1在神经元损伤后表达上调，下调Arc/Arg3.1表达可加重损伤，并增加代谢型谷氨酸受体在细胞膜表面的表达。结合文献报道，我们推测Arc/Arg3.1可能通过调控谷氨酸受体的表达与功能，影响TBI后的兴奋性神经毒性。本课题拟在以往工作基础上，研究TBI后Arc/Arg3.1的表达变化及作用，阐明Arc/Arg3.1调控TBI后谷氨酸受体表达和功能的分子机制及其与其他突触后蛋白的相互作用。本研究对深入了解TBI后继发性脑损伤机制、扩展Arc/Arg3.1的临床应用价值均具有重要意义。

创伤性脑损伤（TBI）有较高的发生率和死亡率，是创伤中最严重的一类。研究表明，谷氨酸受体介导的兴奋性毒性是TBI后继发性脑损伤的重要原因，但其分子机制尚未阐明，且缺乏有效的药物干预措施。Arc/Arg3.1是一种神经元特异性突触后蛋白，介导突触间信号转导，参与学习和记忆等生理过程。我们研究发现，Arc/Arg3.1在神经元损伤后表达上调，下调Arc/Arg3.1表达可加重损伤，并增加代谢型谷氨酸受体在细胞膜表面的表达。结合文献报道，我们推测Arc/Arg3.1可能通过调控谷氨酸受体的表达与功能，影响TBI后的兴奋性神经毒性。本项目在以往研究基础上，系统研究了Arc/Arg3.1在TBI后神经损伤和神经功能障碍中的作用及相关机制。我们发现，TBI后Arc/Arg3.1蛋白表达明显增高，其表达水平受到上游分子RNF216、离子型谷氨酸受体NMDAR和代谢型谷氨酸受体mGluR5的调控。使用慢病毒转染的方法在神经元上过表达Arc/Arg3.1后，可以通过离子型谷氨酸受体AMPAR和代谢型谷氨酸受体mGluR1，影响神经元细胞内钙离子稳态，进而减轻内质网应激和程序性坏死，对TBI后神经损伤发挥保护作用。本研究对深入了解TBI后继发性脑损伤机制、扩展Arc/Arg3.1的临床应用价值均具有重要意义。