Activin A调控小胶质细胞极化行为参与脑缺血再灌注损伤作用机制研究

Ischemia/reperfusion (I/R) injury is the main reason that limits the recanalization treatment of acute cerebral ischemia after thrombolysis and endovascular intervention. Therefore, finding effective methods that attenuate I/R injury is important for the anti-ischemic therapy. Emerging studies showed that microglial polarization (M1/M2 phenotype switch) plays different roles in the process of I/R. But the mechanism behind it is still unclear. In our previous study, Activin A (ActA), as a widely accepted neuroprotective factor, performed a self-limiting neuroprotective effect on nerve cells after ischemic injury. However, the self-limiting behavior of ActA could not explain its delayed cerebral protection in ischemia, suggesting that nerve cells were not the only target of ActA. Moreover, a pre-experiment has been introduced to confirm the effect of ActA on microglial polarization in vitro. Based on these fundations and preliminary results, the relationship between microglial polarization and the pathological outcome of cerebral I/R injury will be studied with the use of I/R model in vivo and in vitro. Furthermore, the signal transduction mechanism and functional sites underlying ActA signaling will be explored durning microglial polarization. These studies would explain the function and mechanism of microglial polarization in I/R injury, and provide ActA related molecular switch for further translational application.

脑缺血再灌注（I/R）损伤是急性脑梗死溶栓及血管内治疗过程中影响血管再通疗效的主要原因之一。因此，寻找能够减轻血管再通后I/R损伤的有效手段非常重要。研究发现小胶质细胞极化行为（M1/M2表型转化）在脑I/R损伤中具有“双刃剑”功能，但机制不清。课题组前期发现，作为较公认的神经保护因子，激活素A（Activin A, ActA）介导的神经元靶向抗缺血损伤信号具有自限性，无法解释其延时的脑保护作用，提示ActA作用靶点不限于神经元。课题组基于此现象的预实验进一步证实ActA可诱导小胶质细胞极化。本项目拟从前期线索切入，在体内外脑I/R损伤模型中，研究小胶质细胞极化行为与脑I/R损伤病理转归方向性的关系。在此基础上以ActA信号为靶点，重点研究可能调控小胶质细胞极化行为的相关信号转导模式和功能位点。深入解释小胶质细胞极化在脑I/R损伤中的作用和分子机制，为相关转化医学研究提供新的分子开关靶点。

脑卒中严重危害人类健康，虽近年来溶栓及血管内治疗进展迅速，但与血管再通相伴随的脑缺血再灌注损伤仍构成限制其急性期疗效的主要原因之一。研究发现小胶质细胞极化行为（M1/M2表型转化）在脑缺血再灌注损伤中具有“双刃剑”功能，但机制不清。课题组前期发现，作为较为公认的神经保护信号介导因子，激活素A（Activin A, ActA）的神经元相关抗缺血损伤信号具有自限性，无法解释其延时神经保护作用，提示其作用靶点不限于神经元。课题组基于此现象的预实验进一步证实了Act A可诱导小胶质细胞极化。本项目从前期线索切入，在体内外脑缺血再灌注损伤模型中，研究了小胶质细胞极化方向性与脑缺血再灌注损伤过程发展方向的关系。在此基础上以Act A信号为靶点，重点研究可能调控小胶质细胞极化行为的相关信号转导模式和功能位点。研究结果显示缺血性脑损伤可诱导小胶质细胞的极化，缺血早期以M2型为主，后期以M1型为主；Act A/Smads信号通路的活化可诱导小胶质细胞表型从M1型向M2型转化，这种变化可能发挥抗缺血损伤作用，为缺血性脑损伤的治疗提供潜在的转化靶点。