缺血性脑损伤致死致残率高，如何促进脑缺血后损伤修复是目前研究热点。成体内源性神经干细胞(endogenous neural stem cells, eNSCs)具有向伤灶迁移参与修复的能力，但调控机制不清楚。在前一国自然的支持下，我们发现eNSCs特异性表达酸敏感离子通道ASIC1a和2a亚基，并形成有功能的通道，应用药理和基因敲除等方法显示：脑缺血后微环境酸化通过激活ASIC1a抑制eNSCs的迁移。为深入阐明内在的分子机制，本项目拟采用形态学、分子生物学、活细胞动态观察、基因工具鼠等方法从细胞、脑片、动物模型等层次，系统研究ASIC1a介导脑缺血后酸化对eNSCs迁移的调控作用及机制，重点揭示“RhoA/Myo10/F-actin/filopodia”信号通路在其中的作用。通过本研究不仅利于深化对eNSCs迁移调控机制的认识，而且为研发促eNSCs参与损伤修复的策略提供科学依据。

Ischemic brain injury remains a leading cause of death and disability. Research on the neurorestoration after ischemia is a hot field. Adult endogenous neural stem cells (eNSCs) located in the subventricular zone will be activated to migrate into the lesion site to repair the injury after ischemia. However, the underlying mechanisms remain largely unknown. Supported by the previous grant from national Natural Science Foundation of China, we showed that acid sensing ion channel (ASIC) subunit ASIC1a and ASIC2a are specifically expressed by eNSCs, forming funtional channel. Pharmacological and genetic data showed that acidification after ischemic stroke activates ASIC1a on eNSCs to impair their migrtion potential. To clarify the intrinsic molecular mechanisms involved in this process, we will employ morphorlogical, molecular biological, live cell imaging system and genetic approaches to disclose the underlying mechanisms mediating ASIC1a activation induced inhibition of eNSCs migration after ischemic stroke. We will focus on the molecular pathway in which ASIC1a activation activates RhoA, signaling to Myosin 10 and F-actin, to influence the filopodia and migration of eNSCs. This study will not only help to elucidate the mechanisms controlling the migration of eNSCs, but also provide evidence for the development of therapeutic strategy via enhancing eNSCs migration into ischemic area after ischemic stroke.