Pmepa1减少缺血半暗带神经元损伤改善卒中预后的作用机制

Penumbra neuron injury is highly associated with the prognosis of ischemic stroke. Neurons in the ischemic penumbra are in the state of electrical failure, although the neuronal function is abnormal, they are still viable. The improvement of ischemic penumbra neuron state and function directly influences the outcome of stroke. Previous studies have found that Pmepa1 was involved in regulating neurogenesis and maintaining neuronal function, but its role in neuron injury after ischemic stroke has not been clarified. In the preliminary proteomic studies, we have identified that the expression of Pmepa1 was significantly decreased in the cerebral ischemic penumbra region, while overexpression of Pmepa1 could alleviate the death of ischemic penumbra neurons caused by calcium overload and improve the nerve function after ischemic stroke in mice. In this study, we aim to: 1) confirm the effect of Pmepa1 on the neuronal function in ischemic penumbra; 2) investigate whether the regulatory effect of Pmepa1 on ischemic penumbra neurons is related to calcium overload; 3) further elucidate the possible molecular mechanism of Pmepa1 regulating calcium overload. We hope our study can elucidate the effect of Pmepa1 on ischemic penumbra neuron injury and reveal Pmepa1 may be a potential therapeutic target for ischemic stroke.

缺血半暗带神经元损伤与卒中预后密切相关。缺血半暗带神经元处于电衰竭状态，虽然功能异常但尚未死亡，改善其状态和功能直接影响卒中转归。既往研究发现Pmepa1参与调控神经元发育和维持神经元功能稳定，但其在缺血性卒中后神经元损伤中的作用尚未阐明。我们前期通过蛋白质组学研究发现，缺血半暗带Pmepa1表达显著下降；而过表达Pmepa1可以减少钙超载引起的缺血半暗带神经元死亡，改善小鼠缺血性卒中后神经功能损伤。本课题拟通过行为学、免疫荧光、电生理等技术，解决以下问题：1）明确Pmepa1对缺血半暗带神经元功能状态的影响；2）探索Pmepa1对缺血半暗带神经元钙超载的调控作用；3）进一步阐明Pmepa1调控钙超载改善缺血半暗带神经元损伤的可能分子机制。本项目首次研究Pmepa1对缺血半暗带神经元损伤的调控作用，揭示Pmepa1可能是缺血性卒中的潜在治疗靶点，为缺血性卒中早期治疗提供的依据。

缺血半暗带神经元损伤与卒中预后密切相关。缺血半暗带神经元处于电衰竭状态，虽然功能异常但尚未死亡，改善其状态和功能直接影响卒中转归。既往研究发现Pmepa1参与调控神经元发育和维持神经元功能稳定，但其在缺血性卒中后神经元损伤中的作用尚未阐明。本课题通过行为学、免疫荧光、电生理等技术研究发现，缺血性卒中后Pmepa1表达显著下降；进一步研究发现Pmepa1可通过减少炎症因子释放、减轻BBB破坏、减轻兴奋性氨基酸毒性及钙超载等多种途径发挥缺血性脑损伤保护作用。而过表达Pmepa1可以通过NEED4减少钙超载引起的缺血半暗带神经元死亡，改善小鼠缺血性卒中后神经功能损伤。本项目首次研究Pmepa1对缺血半暗带神经元损伤的调控作用，揭示Pmepa1可能是缺血性卒中的潜在治疗靶点，为缺血性卒中早期治疗提供的依据。