ClC-3氯通道广泛分布于哺乳动物的脑组织细胞中，包括神经元、胶质细胞、血管内皮细胞和血管平滑肌细胞，并参与细胞容积调节、细胞增殖、分化以及凋亡等多种病理生理进程的调节。本项目拟在前期研究发现ClC-3基因敲除加重小鼠局灶性脑缺血再灌注损伤，并显著增加缺血脑区神经元丢失和小胶质细胞活化反应的基础上，从整体、细胞和分子水平系统研究ClC-3氯通道对脑内星形胶质细胞的能量代谢、氧化应激、胶质传递等功能及对小胶质细胞炎症与免疫反应的调节，阐明ClC-3氯通道在缺血性脑卒中发生发展中的作用。研究成果不仅有助于深化对缺血性脑卒中病理机制的认识，也为研发理想有效的多潜能的脑卒中神经保护剂提供新靶标。

ClC-3 has been found ubiquitously expressed in the mammal central nevous system, including neuron, glial cell, endothelium and vascular smooth muscle cells. ClC-3 functions as a crucial modulator in various pathophysiologic process, such as cell volume regulation, cell proliferation, migration and apoptosis. Our previous study showed that ClC-3 knockout aggravated focal cerebral ischemia and reperfusion injury in mice, with significant increase of neuronal apoptosis and microglial activation. In the present study, we intend to explore the regulating effects of ClC-3 on astrocyte-mediated energy metabolism, oxidative stress, gliotransmission, and microglia-mediated inflammatory immunoregulation. Furthermore, the investigation contributes to clarify the roles of ClC-3 in the pathologic process of stroke. These works will give us a novel insight into the pathologic mechanisms of ischemic stroke, and a potential target for multi-potential neuroprotectants.

ClC-3氯通道属于容积调节性氯通道（Volume-regulated Cl- channels，VRCCs），广泛分布于哺乳动物脑组织的神经元、胶质细胞、血管内皮细胞和血管平滑肌细胞等，并参与多种病理机制的调节。前期研究发现：ClC-3基因敲除加重小鼠局灶性脑缺血再灌注急性期损伤并促进小胶质细胞的活化。本项目进一步从整体、细胞和分子水平系统研究了ClC-3氯通道对胶质细胞的调节及其与脑缺血损伤的相关性。研究发现：（1）ClC-3氯通道阻断剂（DIDS和NPPB）能够促进OGD所致小胶质细胞向M2型转化，从而减轻氧糖剥夺（oxygen-glucose deprivation, OGD）诱导的小胶质细胞的炎性反应，该过程与自噬相关；（2）ClC-3氯通道阻断剂显著改善OGD诱导的星形胶质细胞的损伤与炎性反应；（3）脑内局部给予DIDS显著改善小鼠局灶性脑缺血再灌注损伤；（4）ClC-3基因部分缺失减轻小鼠局灶性脑缺血再灌注损伤及神经运动功能障碍。上述研究结果揭示了ClC-3氯通道对胶质细胞的调节及其在脑缺血损伤中的重要作用。研究结果不仅有助于深化对脑缺血急性期损伤的病理机制的认识，也为脑卒中治疗药物的研发提供了新靶标。