反应型星形胶质细胞在阿尔茨海默病（AD）病理过程中起着关键作用。AD进程中反应型星形胶质细胞失去促进神经元存活和突触形成等能力，进而引发神经元死亡。我们以往研究发现AD患者脑内高表达的KCa3.1参与反应型星形胶质细胞表型转化进而介导神经元毒性作用，然而其确切调控机制仍未阐明。本项目拟在前期发现星形胶质细胞KCa3.1和钙通道Orai1存在相互作用参与钙库操纵性钙内流（SOCE）的基础上，应用脑库AD患者样本、KCa3.1-/-/APP/PS1 AD小鼠模型，以及星形胶质细胞-神经元共培养体系，在人脑库样本-动物整体-细胞-分子水平系统研究KCa3.1/Orai1信号复合物表达变化与反应型星形胶质细胞内质网应激的相关性，阐明KCa3.1/Orai1信号复合物通过SOCE调控反应型星形胶质细胞钙超载引起内质网应激介导神经炎症的分子机制，为AD治疗新靶点及其新药研发提供理论基础。

Reactive astrocytes play an important role in the pathogenesis of Alzheimer's disease (AD). We found the up-regulation of calcium-activated potassium channel KCa3.1 in AD patients’ brains. KCa3.1 was involved in the phenotype switch of reactive astrocytes. However, the role of KCa3.1 during the phenotype switch of astrogliosis is not clear. Our unpublished data indicated the interaction between KCa3.1 and Orai1 in the astrocytes, and KCa3.1/Orai1 signaling complex participated in the process of store-operated calcium entry (SOCE). This study will utilize the brain bank of AD patients, KCa3.1-/-/APP/PS1 AD mouse model, co-culture system of neuron-astrocyte to determine the relationship between KCa3.1/Orai1 and endoplasmic reticulum (ER) stress of astrogliosis in AD. Our study will clarify the mechanism of KCa3.1/Orai1 in regulating ER stress of astrogliosis via the SOCE in AD and provide a basis for KCa3.1 channel as AD therapy target and new drug discovery.