HMGB1通过调节BBB通透性参与放射性脑损伤过程的实验研究

项目名称： HMGB1通过调节BBB通透性参与放射性脑损伤过程的实验研究

项目编号： No.81501040

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周海红

作者单位： 广东医科大学

项目金额： 17.5万元

中文摘要： 炎症反应引起血脑屏障(BBB)破坏是放射性脑损伤(RBI)重要启动环节之一，因此研究调节BBB通透性的分子机制非常重要。近年研究显示高迁移率族蛋白B1(HMGB1)这一强烈的炎症刺激因子可作为阻断神经炎症和BBB 破坏的理想靶标。课题组前期研究发现RBI鼠脑脊液中HMGB1含量明显增高，且与神经功能损伤程度呈正相关，侧脑室注射HMGB1中和抗体显著减轻BBB破坏。由此我们推测，HMGB1通过与其受体结合参与RBI发生发展过程，以其为靶点进行阻断可减轻BBB破坏及缓解神经炎症。本课题拟：①建立离体BBB放射性损伤模型和RBI大鼠模型，检测HMGB1及炎症因子表达、BBB通透性改变；②分别阻断HMGB1及其受体RAGE、TLR4，利用行为学、分子生物学、形态学等方法观察BBB通透性、神经炎症反应及神经功能损伤；③分析确认HMGB1影响BBB通透性的可能机制，为寻找新的治疗靶点提供实验依据。

中文关键词： 放射性脑损伤；高迁移率族蛋白B1；血脑屏障；晚期糖基化终产物受体；Toll样受体

英文摘要： The blood brain barrier injury induced by inflammation is an important activated process of radiation brain injury (RBI). Recent studies have shown that a high mobility group protein B1 (HMGB1), which is a strong inflammatory stimulus, can be used as the ideal target to block the neuroinflammation and protect BBB. However, the roles of HMGB1 in RBI are poorly understood. In preliminary studies, we found that the content of HMGB1 significantly increased in cerebrospinal fluid of RBI rats, which was positively associated with neurologic impairment. BBB permeability was improved after the injection of the neutralizing antibody against HMGB1 into the lateral ventricle. In the present study, we aim firstly to investigate the role of HMGB1 in the regulation of BBB permeability during RBI by using BMEC-AC co-culture and RBI animal model. We will further study the possible mechanism of HMGB1 to regulate the permeability of BBB and neuroinflammatory reaction by blocking HMGB1 and its receptors, receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4 ). The study would provide evidence for targeting HMGB1 as the further treatment strategy of RBI.

英文关键词： radiation-induced brain injury;HMGB1;Blood Brain Barrier;RAGE;Toll like receptor