Homer1a介导AMPAR-CREB通路对放射性脑损伤后神经保护作用的分子机制研究

Radiation-induced brain injury, as a complication of radiotherapy, causing severe obstacles in patients with increasing survival rate of brain tumors after radiotherapy. The current treatments could not work well. Mechanisms of radiation-induced brain injury is very complex, including apoptosis, oxidative stress, and calcium overload. Homer1a as an immediate early gene may play an important role in neurodegenerative diseases and chronic anxiety. A recent study found Homer1a was regulated after radiation-induced brain injury in cortical and hippocampal neurons, but the mechanism was not stated. Our previous studies showed that Homer1a probably played a protective role in brain injury. Proteomic analysis demonstrated regulating Homer1a could activate AMPAR-CREB pathway in nerve cells, thus affecting synaptic plasticity, cognitive and neurological functions. Based on these findings, this project will employ technology of gene knockout and overexpression, combined with proteomics, cell biology, animal behavior, and other methods to systematically prove Homer1a effect through AMPAR-CREB pathways after radiation-induced brain injury, as well as the effects on nerve function and prognosis. This study may open up a novel idea for treatment of radiation-induced brain injury and provide a theory basis for diagnosis and treatment.

虽然颅脑肿瘤放疗患者生存率日渐提高，但放射性脑损伤作为放射治疗的主要并发症，对患者造成严重的生活障碍，而且其治疗收效甚微。放射性脑损伤的分子机制十分复杂，研究表明，Homer1a在放射性损伤模型中，可能对皮层和海马神经元发挥保护作用，但其具体机制并不清楚。课题组前期研究结果证实，放射性损伤后，小鼠皮层、海马区中Homer1a表达均出现短期升高，通过干涉Homer1a的表达，可调节GluR、ERK、CREB分子的磷酸化激活及神经细胞程序性死亡进程。基于我们的以上发现，本项目将充分运用质谱，对比分析Homer1a表达变化的生物信息学结果，结合细胞生物学、动物行为学等手段，系统阐明放射性脑损伤后Homer1a介导AMPAR-CREB通路对神经细胞的作用机理，以及对其功能和预后的影响，为诊、治放射性脑损伤开辟新思路。

放射治疗在颅脑肿瘤的治疗中拥有独特的优势，但在治疗肿瘤的同时可能对脑部造成放射性损伤。目前，急性放射损伤和亚急性放射损伤可通过内科治疗达到有效控制，而针对迟发性放射脑损伤的治疗却一直收效甚微。迟发性放射脑损伤主要表现为脑坏死、智能减低、记忆力障碍、严重者痴呆甚至死亡。据统计，迟发性放射脑损伤发生率超过50%，严重影响放疗患者的生活质量。随着放疗技术的不断进步，脑肿瘤患者长期生存率大幅提高，但迟发性放射脑损伤的治疗问题日益凸显，作为慢性发展性疾病，其治疗关键究竟是什么？. 我们的前期研究结果发现，放射损伤后，小鼠脑皮层和海马区及原代神经元中Homer1a会出现差异性表达，Homer1a慢病毒干涉载体可下调神经元中Homer1a的表达，加重神经元损伤和细胞死亡；过表达载体可上调神经元Homer1a表达，显著减轻神经元损伤和死亡。后续利用质谱分析发现，调节神经元中Homer1a的表达，可调控AMPAR-CREB通路中GluR、ERK、CREB分子的磷酸化激活，进而影响神经元凋亡和突触可塑性等。通过动物行为学试验，放射性损伤后，使小鼠的焦虑水平升高，能够导致小鼠的空间学习记忆受损，提示辐照可能损伤了海马功能。Homer1a可能在大脑皮层和海马区中调节AMPAR-CREB通路，从而在放射性脑损伤中发挥关键性作用。有助于发现放射性脑损伤的发生发展规律，寻找新的治疗作用靶点，对放射性脑损伤的早期诊断与治疗具有重要意义。