缺血性脑损伤中组胺H2受体对小胶质细胞的调控作用及机制研究

The pathophysiology of ischemic brain injury is very complex and the therapeutic options remain very limited at present. Our previous studies have found that histamine H2 receptor (H2R) plays a protective role by targeting different aspects of cerebral ischemia, making it a potential target. However, there are still contradictions about the role of H2R, so it is necessary to investigate its role in specific cells. The regulation of the function of microglia has become a key problem in current research. Migration and phagocytosis are important process for the function of microglia. Our previous works found histamine provided neuroprotection after cerebral ischemia through H2R, and interestingly found that H2R might be associated with the shape and migration of microglia. Meanwhile, it's reported that H2R participated in the regulation of phagocytosis of microglia. Therefore, histamine H2R may be a new target for the neuroprotective effect by targeting microglia. In addition, we found H2R bound with the important protein Rab5C related to phagocytosis and migration, suggesting the possible mechanism of H2R in the regulation of microglia. To further understand the exact role of H2R in the regulation of microglia after cerebral ischemia, our project intends to knock out or overexpress H2R in microglial with conditional knockout mice and lentiviral vector technology and then make evaluation in vivo/vitro ischemia model through different technology. The present research would help to make better understand of H2R's role in the regulation of microglia after cerebral ischemia and give light to potential drug targets.

缺血性脑损伤的病理机制十分复杂，目前无有效治疗方案。前期研究发现组胺H2受体（H2R）是潜在治疗靶点，但存在矛盾之处，因此需研究特定细胞中H2R的作用。调控小胶质细胞的功能已成为研究热点，迁移和吞噬是其发挥功能的重要环节。项目前期发现缺血后组胺通过H2R发挥保护作用，并意外发现H2R可能与小胶质细胞形态及迁移相关。文献提示H2R调控小胶质细胞吞噬功能。因此，H2R可能是靶向小胶质细胞发挥神经保护作用的药物新靶点。进一步实验发现H2R与吞噬及迁移相关的重要蛋白Rab5C存在相互作用，提示H2R调控小胶质细胞的可能机制。基于此，项目拟采用整体及离体缺血再灌注模型，利用Cx3cr1CreER:H2Rfl／fl工具鼠及慢病毒载体技术，特异性敲除与过表达小胶质细胞H2R，明确H2R在脑缺血后对小胶质细胞的调控作用，并探索Rab5C相关机制，以期为认识缺血性脑损伤发病机制、寻找精准药物新靶点作出贡献。

缺血性脑损伤的病理机制十分复杂，目前无有效治疗方案。前期研究发现组胺H2受体（H2R）是潜在治疗靶点，但存在矛盾之处，因此需研究特定细胞中H2R的作用。调控小胶质细胞的功能已成为研究热点，迁移和吞噬是其发挥功能的重要环节。项目前期发现缺血后组胺通过H2R发挥保护作用，并意外发现H2R可能与小胶质细胞形态及迁移相关。文献提示H2R调控小胶质细胞吞噬功能。因此，H2R可能是靶向小胶质细胞发挥神经保护作用的药物新靶点。本项目研究了缺血后H2R对小胶质细胞细胞的调控作用，主要成果如下：①明确了缺血后不同时间点小胶质细胞中Hrh2的表达水平的变化，分析了小胶质细胞中吞噬与迁移相关的通路，明确了吞噬与迁移核心基因与Hrh2的相关性；②明确了H2R与迁移和吞噬相关蛋白Rab5C在体内存在相互作用，分析了Rab5c在缺血后不同时间点的表达水平，进一步构建了H2R和Rab5C在缺血后调控小胶质细胞迁移及吞噬的蛋白互作网络，为H2R在缺血后调控小胶质细胞迁移和吞噬提出了可能的机制；③参与培养博士研究生2名；④发表SCI论文3篇。