酸敏感离子通道 ASIC3 对缺血性中风侧支循环的改善作用及机制研究

及早恢复或改善缺血区脑血流灌注是治疗缺血性中风的重心。侧支循环作为组织缺血后为阻塞动脉供血区提供血流的生理性旁路途径，是改善脑血流灌注的一条重要途径。局部H+浓度变化是脑血流调节的重要影响因子之一。酸敏感离子通道3（ASIC3）对胞外H+变化非常敏感，近期有文献报道ASIC3在外周缺血性损伤中有保护作用。我们在皮层脑血管壁发现有来源于三叉神经节ASIC3神经元的纤维末梢分布，敲除ASIC3加重小鼠脑缺血梗死体积和脑水肿，增加死亡率，减少缺血区侧支循环的建立和血流供应，恶化神经行为学评分。我们推测ASIC3的脑保护作用与其促进侧支循环开放和改善缺血区血流有关。我们将在动物模型和离体实验中通过分子生物学、电生理、血流成像、形态学、基因工程等手段，阐明ASIC3在脑中的表达定位，解析其在中风后侧支循环开放中的的作用和机制，并以ASIC3为靶点进行药物开发。

Collateral enhancing strategies are important ways to restore blood flow within ischemic regions, particularly in patients who are ineligible for revascularization therapy. Local H+ concentration plays a significant role in regulation of cerebral blood. Acid-sensitive ion channel 3 (ASIC3) as the most sensitive ASIC subtype responding to extracellular H+, has been reported to has a protective effect against ischemic injury. We found the nerve fibers from ASIC3 neurons in trigeminal ganglion are present in the wall of cerebral blood vessels; ASIC3 knock out increases the infarction and cerebral edema, increases mortality, and reduces the collateral circulation to deteriorate the outcome. We propose that the protective effect of ASIC3 is associated with its role in improvement of collateral circulation and restoration of blood flow to the ischemic area. In the present project, we will clarify the expression of ASIC3 in brain, investigate the signaling pathway underlying collateral enhancing, and confirm the therapeutic effect of ASIC3 agonist GMQ. This project will expand the research on the function of ASIC3, and provide new target for the treatment of ischemic stroke.