CCR2阳性单核/巨噬细胞促进脑缺血长期神经功能恢复的机制及其药物干预研究

项目名称： CCR2阳性单核/巨噬细胞促进脑缺血长期神经功能恢复的机制及其药物干预研究

项目编号： No.81673442

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 方伟蓉

作者单位： 中国药科大学

项目金额： 25万元

中文摘要： 脑缺血诱导的炎症反应是研究热点，调控巨噬细胞极化会影响炎症转归，但在脑缺血长期神经功能恢复中的机制尚未阐明。前期研究表明，CCR2阳性单核/巨噬细胞在脑缺血急性期加重梗死，然而长期却维持动物存活、促进神经功能恢复，其机制与巨噬细胞M1/M2型极化有关。本项目旨在用CCR2基因敲除小鼠及其CCR2抑制剂，阐释CCR2阳性单核/巨噬细胞对脑缺血长期恢复的影响；应用流式细胞分选、免疫荧光等技术研究脑缺血后巨噬细胞极化过程，揭示M1/M2比例的动态变化与促炎/修复的内在关系；用M2巨噬细胞过继移植，阐明脑缺血后M2巨噬细胞促进神经修复的功能；用IL-4 complex、XQ-1H等药物干预，探讨IL-4→pSTAT6→PPARγ信号通路调控M2巨噬细胞极化及其促进脑缺血长期恢复的分子机制。研究结果将揭示脑缺血后长期神经功能恢复的潜在治疗靶点，并为调控M2巨噬细胞极化的相关药物研究建立平台。

中文关键词： CCR2；脑缺血；巨噬细胞；极化；长期恢复

英文摘要： Ischemic stroke induced inflammation is a main focus in current research. Regulating macrophage will facilitate inflammation recovery, but it is still unknown in long term recovery after ischemic stroke. Our previous research showed that CCR2 expressing monocyte/macrophage aggravated infarct size in acute stage, while sustained survival and promoted long term recovery after ischemic stroke. The underline mechanism may be related to M1/M2 macrophage polarization. In this project, we will set up ischemic stroke model in CCR2 knockout, and wild type mice. Long term survival, behavior and memory test will be observed to verify the effect of CCR2 expressing monocyte/macrophage on long term recovery from ischemic stroke. We will use flow cytometry analysis, sorting, and immunofluorescence to study M1/M2 macrophage polarization in different time after ischemic stroke. The results will indicate the relationship between M1/M2 macrophage ratio and proinflammatory/tissue repair conversion. We will apply M2 macrophage adoptive transfer to explore the function of M2 macrophage after ischemic stroke. At last, we will use some medicine, such as IL-4 complex, XQ-1H, to approve the signal pathway IL-4→pSTAT6→PPARγ which will stimulate M2 macrophage polarization both in vivo and in vitro. The expectant results of this project will reveal the potential target on long term recovery from ischemic stroke, and will give evidence to M2 macrophage polarization target medicine on ischemic stroke treatment.

英文关键词： CCR2;isehemic stroke;macrophage;polarization;long term recovery