Homer1a 蛋白激活自噬保护脑创伤神经元的分子机制研究

Autophagy is intimately engaged in the process of brain trauma, and the occurrence of autophagy is directly related to the prognosis of traumatic brain injury, but the underlying mechanisms is still largely unknown. Our previous study confirmed that Homer1a has a protective effect on neurons in the brain after trauma, and autophagy is been activated, but the mechanisms between Homer1a and protective effects and its molecular links remain unclear. Based on the results, our study intend to detect the expression of Homer1a in traumatic neuron injury, to explore the effect on the protective effects of homer1a against neuron injury, to clarify the mechanism of protective effects of homer1a through the activating of autophagy mediated by NR2B/PI3K-AKT-mTOR pathway and the interaction between autophagy and Homer1a through a series of molecular biological methods. It provides a novel insight into the mechanism of protection of traumatic neuronal injury and may contribute to the development of therapeutic applications.

自噬与脑创伤关系密切相关，脑创伤发生后，自噬的发生发展与脑创伤的预后直接相关，但其关键分子和作用机制尚不明确。我们前期研究证实，Homer1a在脑创伤后对神经元有保护作用，且能够激活自噬，但其保护神经元机制及其和自噬的关系及分子联系仍然不清楚，因此，本研究拟采用分子生物学方法：1、检测创伤性神经元损伤后Homer1a表达， 明确其与创伤性损伤相关性；2、检测神经元损伤后自噬相关分子表达，明确自噬与创伤性神经元损伤关系；3、通过过表达和沉默Homer1a基因，验证Homer1a和自噬在创伤性神经元损伤模型中的关系；4、通过研究自噬相关分子和信号通路NR2B/PI3K-AKT-mTOR活化、强弱的变化，找出Homer1a激活自噬的相关靶点，为揭示创伤性神经元损伤的分子机制及其治疗提供新的理论依据。

外伤性脑损伤（TBI）是最常见的神经系统疾病，导致急性神经元损伤，导致脑损伤和神经功能缺损。我们前期研究证实，Homer1a在脑创伤后对神经元有保护作用，且能够激活自噬。自噬与脑创伤关系密切相关，脑创伤发生后，自噬的发生发展与脑创伤的预后直接相关。我们分别用大鼠和分离的神经细胞建立了TBI的体内和体外模型，实验结果发现：(1)过表达Homer1a通过通过抑制ERK1/2的激活拮抗神经元的机械性损伤；(2)在体内和体外诱导TBI后，TBI大鼠自噬小体结构增加(3)Homer1a过表达上调了体内外自噬相关蛋白LC3II和Beclin 1的表达；(4)通过过表达和抑制Homer1a基因，验证Homer1a在创伤后激活了自噬，通过调节信号通路PI3K-AKT-mTOR，最终影响神经元存活。