星形胶质细胞表达的离子通道在缺血性中风时的功能性变化及其相关作用

K+ channels including the inward-rectifier K+ (Kir) channels and the voltage-gated K+ (Kv) channels have been found ubiquitously expressed in the neuroglia including oligodendrocytes, astrocytes and microglia. K+ channels play crucial role in many pathophysiologic processes in astrocytes such as potassium spatial buffering, glutamate clearance, cell volume regulation and cell proliferation. Our primary study generated induced pluripotent stem cells from human fibroblasts and successfully differentiate them to astrocytes (i.e., human IPSC-Derived astrocytes). In the present study, we intend to use human IPSC-Derived astrocytes to explore the molecular and cellular mechanism, particularly the roles of K+ ion channels in the pathologic process of stroke. We will perform the functional characterization of variable types of ion channels expressed in human astrocytes. We will also examine the altered ion channel function under ischemic conditions (oxygen and/or glucose deprivation and/or extracellular acidification). Furthermore, we will study the mechanism underlying the altered function of ion channels and their correlation to the pathophysiologic processes in stroke. These works will give us a novel insight into the pathologic mechanisms of ischemic stroke in human glial cells, and potential targets for anti-stroke therapeutics.

神经胶质细胞包括星形细胞、寡突细胞及小胶质细胞，其主要表达的离子通道为两类钾离子通道，包括内向整流钾离子通道(Kir)和电压门控钾离子通道(Kv) 。胶质细胞上表达的钾离子通道决定了细胞静息膜电位，并能够调节细胞外的K+浓度，谷氨酸的清除，细胞容积，细胞增殖和细胞死亡等多种病理生理进程。在前期研究中，人的成纤维细胞被成功转化成诱导性干细胞，并能够分化成人的星形胶质细胞，该项目从细胞和分子水平，特别是离子通道功能性(电生理)的角度，系统研究：1）离子通道在人的诱导性干细胞分化成的星形胶质细胞上的功能性表达及其分子基础，2）在缺血性中风发生条件下，其主要离子通道的功能性变化和变化的机制，3）特定离子通道的功能性变化与缺血性中风病理进程的相关机制研究。 研究成果不仅有助于深化对在人脑中缺血性中风病理机制的认识，也为研发有效的多潜能的中风神经保护剂提供新靶标。

星形胶质细胞具有各种K+通道的丰富表达，可调节大脑中神经元的兴奋性和细胞外稳态，急性缺血性中风会严重损害神经元和星形胶质细胞的功能。星形胶质细胞钾通道在缺血性中风中的病理作用尚不清楚。研究结果表明人类星形胶质细胞有内向整流钾离子通道和电压门控钾离子通道的功能性表达，长期暴露于缺血溶液，星形胶质细胞中A型K+通道的功能性表达降低。该结果揭示了星形胶质细胞Kv4.2可能在缺血性中风的发病机制中发挥重要作用。同时，关于脑病治疗的研究，我们还探讨了在鱼藤酮和MPP+诱导的慢性帕金森病（PD）小鼠模型中，温肾养肝汤和紫锥菊苷对多巴胺能（DA）神经元损伤的保护作用及机制。结果表明温肾养肝汤可以保护小鼠免受鱼藤酮诱导的慢性PD，这可能与DA神经元凋亡的减少，以及抑制炎症反应和神经元凋亡途径有关。紫锥菊苷可修复MMP+诱导的神经元损伤，降低细胞毒性作用，与对自噬相关蛋白的调控有关。另外，我们还从凋亡的角度初步研究了类固醇5α还原酶І（Steroid 5α-reductase type I, SRD5A1）与多发性骨髓瘤（MM）发生发展的关系，发现SRD5A1在骨髓瘤中的高表达水平预示着骨髓瘤患者预后较差，同时SRD5A1促进了骨髓瘤细胞的增殖，揭示了其在骨髓瘤中致癌基因的作用。