脑出血炎症反应上调铁调素的表达影响脑铁清除及机制

项目名称： 脑出血炎症反应上调铁调素的表达影响脑铁清除及机制

项目编号： No.81471191

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨清武

作者单位： 中国人民解放军第三军医大学

项目金额： 90万元

中文摘要： 降低脑铁沉积是脑出血（ICH）治疗的重要手段，由于目前ICH后脑铁代谢机制及其调控因素不清楚，单纯通过物理方法降铁治疗的效果存在较大差异。因此探索ICH后脑铁代谢机制并进行针对性干预有重要意义。鉴于铁调素在铁代谢中起着重要作用，我们预实验发现ICH后星形胶质细胞铁调素表达显著上调，而且还发现TLR4敲除鼠ICH后铁调素表达及脑铁含量均降低。结合已有研究证实铁调素与血管内皮细胞膜上膜铁转运蛋白（FPN）相互作用在铁代谢中具有重要作用，据此我们提出如下假说：ICH后TLR4介导的炎症反应上调星形胶质细胞铁调素表达，进而与内皮细胞膜上FPN结合，导致脑铁清除受阻。为此本项目拟进行：（1）明确铁调素在ICH后脑铁代谢中的作用；（2）探讨ICH后铁调素表达上调的机制；（3）探索通过抑制铁调素表达、降低脑铁含量对ICH治疗的效果。该研究可进一步阐明ICH后脑铁代谢的机制，可望为ICH的治疗提供新方法。

中文关键词： 脑出血；炎症反应；铁调素；脑铁代谢；Toll样受体4

英文摘要： Reducing the deposited brain iron is one of important measures in treatment of intracerebral hemorrhage (ICH). Currently, as the mechanism of brain iron metabolism and its regulating and controlling factors after ICH are not clear, the effect of the treatment of reducing iron simply by physical method has larger difference. So exploring the mechanism of brain iron metabolism following ICH and giving the targeted intervention have important roles in the ICH therapy. Given that hepcidin plays an important role in iron metabolism, our pre-experiments has also found that the astrocyte expression of hepcidin was significantly increased after ICH, while both of the hepcidin expression levels and the brain iron contents around the hematoma brain tissue were reduced in the TLR4 knockout mice ICH model. Combined with the studies that have confirmed the interactions of the hepcidin and the ferroportin (FPN) expressed on the vascular endothelial cell membrane plays an important role in iron metabolism, thus we put forward the following hypothesis: TLR4 mediated the inflammatory response upregulated the astrocytes expression of hepcidin after ICH, then combined with FPN expressed on the endothelial cell membranes slowing the deposited brain iron's expelling. Therefore based on this, we proposed the further study aims: (1) to explore the role of hepcidin in the brain iron metabolism after ICH; (2) to study the mechanism of the upregulated hepcidin following ICH; (3) to investigate whether TLR4 inhibitors could improve the effect of ICH treatment via inhibiting the hepcidin expression to reduce the deposited brain iron. The study can further elucidate the mechanism of brain iron metabolism after ICH, and is expected to provide new methods for the treatment of ICH.

英文关键词： Intracerebral Hemorrhage;Inflammatory Response;Hepcidin;Brain iron metabolism;TLR4