内质网应激诱导的自噬与凋亡在砷致神经细胞损伤中的作用机制研究

Drinking water endemic arsenism is one of the key endemic diseases in China, and it is also an important public health problem to be solved urgently. Chronic arsenic poisoning can cause abnormal changes in the function of multiple organs before skin lesions, among which the nervous system is more sensitive and is one of the important target organs. In previous studies, the applicant has found that arsenic exposure can lead to endoplasmic reticulum stress in rat nerve cells, but the specific mechanism still needs to be further explored. In combination with the close connection between endoplasmic reticulum stress and autophagy and apoptosis, the applicant has proposed the following scientific hypothesis regarding the mechanism of nervous system damage caused by arsenic. Arsenic can induce ERS in nerve cells, leading to changes in autophagy related proteins, leading to protective effect of autophagy or autophagy death, and at the same time inducing apoptosis cascade reaction. Salubrinal, an ERS inhibitor, was used for intervention, blocking the dephosphorylation process of eIF2, regulating the autophagy reaction process, and inhibiting apoptosis, so as to achieve the protective effect on nerve cells. This study will combine animal experiments and cell experiments to verify the above hypothesis. This not only provides new ideas for the research on the mechanism of arsenic-induced nervous system diseases, but also provides new drug targets for antagonizing arsenic-induced nervous system injuries.

饮水型地方性砷中毒是我国重点防治的地方病之一，也是我国目前亟待解决的重要公共卫生问题。慢性砷中毒在导致皮肤病变之前，可引起多器官功能异常改变，其中神经系统较为敏感，是重要靶器官之一。申请者在以往的研究中发现，砷暴露可以导致大鼠神经细胞发生内质网应激（ERS），但其具体机制还需深入探究，结合ERS与自噬及凋亡的紧密联系，申请者针对砷所导致的神经系统损伤机制提出以下科学假设：砷能够诱导神经细胞发生ERS，导致自噬相关蛋白发生改变，引起自噬性保护作用或自噬性死亡，与此同时诱发凋亡级联反应；利用ERS抑制剂Salubrinal进行干预，阻断eIF2α去磷酸化过程，可调控自噬反应过程，抑制细胞凋亡，从而达到对神经细胞的保护作用。本研究将结合动物实验和细胞实验，验证上述假设。这不仅为砷致神经系统相关疾病的机制研究提供新思路，更为拮抗砷致神经系统损伤提供新的药物靶点。

饮水型地方性砷中毒是我国重点防治的地方病之一，也是我国目前亟待解决的重要公共卫生问题。砷作为一种神经毒物，能够对中枢神经系统造成损害并导致认知功能障碍。申请者在以往的研究中发现砷暴露可以导致大鼠神经细胞发生内质网应激，但其深入的病因机制尚不清楚。本研究应用脑立体定位技术建立大鼠动物模型，内质网应激抑制剂Salubrinal进行干预，采用行为学试验、病理学实验、定量PCR、蛋白印迹、免疫组化等技术研究砷暴露致神经系统损伤的病因机制，探索内质网应激诱导的相关级联反应是否参与其损伤过程；通过体外培养海马神经元细胞以及分子生物学技术进一步验证砷致神经细胞损伤的机制及内质网应激抑制剂Salubrinal对砷损伤神经细胞的保护作用。本研究的主要结果：砷暴露可导致大鼠学习和记忆能力受损，脑组织发生病理改变以及超微结构改变，并可能通过内质网应激相关的PERK-eIF2α-ATF4信号通路诱导海马神经细胞发生自噬；内质网应激抑制剂Salubrinal干预可提高砷暴露大鼠的记忆能力，改善砷暴露大鼠脑组织的病理改变和超微结构改变，并通过调控内质网应激相关信号通路，抑制海马神经细胞的自噬反应。体外培养海马神经元HT-22细胞的结果同样证实，砷通过PERK-eIF2α-ATF4信号通路诱导海马神经元细胞发生自噬，细胞存活率显著降低；Salubrinal干预可以抑制自噬的发生，提高细胞存活率。

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