放射性脑损伤是头颈部肿瘤放疗后严重影响病人生活质量的并发症，但是放射性神经细胞损伤的机制未明。我们在既往发现放疗后神经元可以出现自噬性死亡和凋亡两种死亡形式基础上，通过建立体外和体内放射性神经损伤的模型，探讨放疗后由于细胞的自噬作用不能完全清除ROS的毒性，放疗后脑内产生的ROS通过影响DUSP6的活性，引起ERK1/2活性调节的反馈机制出现障碍，导致ERK1/2活化程度的改变以及其从胞浆向胞核内的核转入水平的变化，从而在胞浆和胞核内分别启动神经细胞的自噬和凋亡两种不同的死亡形式。同时动态观察细胞自噬和凋亡水平的变化，明确放疗后胞浆内和胞核内活化的ERK1/2水平对细胞自噬和凋亡的影响以及两者之间的相互关系。并进一步探讨可能的干预靶点，为今后进一步试图通过清除ROS，增强自噬或干预ERK1/2的活性而保护神经细胞免受放疗所导致的死亡提供新的治疗靶点，为放射性脑损伤的防治提供新的理论依据。

Radiation-induced brain injury (RIBI) is a serious complication which is commonly associated with significant functional morbidity and decreased quality of life in patients treated with brain radiotherapy. The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. Our preliminary studies have found that nerve cells underwent two forms of death, autophagy and apoptosis, after irradiation. In this project, we will establish radiation-induced nerve injury models both in vitro and in vivo, try to clarify that reactive oxygen species (ROS) generated after irradiation inhibit the activity of ERK-specific phosphatases (dual specificity phosphatase 6,DUSP6), which affecting the kinetics of extracellular signal-regulated kinase 1/2 (ERK1/2) activity in a given cellular compartment, provoking a sustained activation of ERK1/2, leading to the progressive accumulation of death-promoting factors up to a level that induces cell death. Sustained cytoplasmic ERK1/2 activity might promote autophagy, whereas sustained nuclear sequestration of ERK1/2 activity might trigger apoptosis. And both autophagy and apoptosis contribute to radiation-induced cellular injury and death. Meanwhile, we will observe the degree of autophagy and apoptosis during cell death at different time points after irradiation, together with the level of cytoplasmic and nuclear activated ERK1/2, to further understand the influence of ERK1/2 on autophagy and apoptosis, and the relationship between autophagy and apoptosis. Furthermore, we will explore interventions such as scavenging ROS, enhancing capacity of autophagy or interfering the activity of ERK1/2, to provide potential therapeutic targets in the treatment of RIBI.