血脑屏障破坏对急性高血压脑水肿形成作用的磁共振动态量化研究

项目名称： 血脑屏障破坏对急性高血压脑水肿形成作用的磁共振动态量化研究

项目编号： No.81471645

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： 高波

作者单位： 东南大学

项目金额： 73万元

中文摘要： 高血压脑病(HTE)是一种可致患者认知障碍和机体残疾的神经系统急症，常合并血脑屏障(BBB)破坏、脑水肿及脑出血。在对HTE、可逆性后部脑病综合征(PRES)前期研究的基础上，我们提出高血压导致毛细血管滤过压增加和内皮细胞功能障碍(ECD)导致BBB破坏是脑水肿形成主要因素的假设，采用micro-MRI动态观察急性高血压大鼠脑水肿分布、动态变化，定量计算脑血流灌注参数及BBB通透性，利用激光多谱勒血流仪动态测定脑血流量(CBF)及血压，实时荧光成像观察BBB通透性，伊文氏蓝判断BBB破坏情况；在不同时间点皮下注射PKCδ抑制剂--V1-1δ，探索PKCδ激活通路在急性高血压导致的ECD、BBB破坏及脑水肿形成中的作用。本研究基于动态定量MRI平台研究BBB破坏及ECD将有助于揭示HTE发病的分子机制，可望成为研究HTE发病机制的重要突破口，为临床治疗提供新靶点，开辟临床治疗的新途径。

中文关键词： 磁共振成像；高血压脑病；发病机制；血脑屏障；蛋白激酶C

英文摘要： Hypertensive encephalopathy (HTE) is a potentially fatal condition associated with blood-brain barrier (BBB) disruption and cerebral edema development. The pathogenesis leading to this condition has not been well addressed and the molecular pathways are unknown either. On the basis of our experimental research on HTE and clinical studies on posterior reversible encephalopathy syndrome (PRES), we put forward the hypothesis of δPKC activation may be a pivotal signaling event which dysregulates structural and functional integrity of tight junctions and BBB disruption leading to brain edema and encephalopathy onset. We determine the role of δPKC on HTE model by infusing subcutaneously δV1-1 selective peptide inhibitor of δPKC.The mortality rate, behavioral symptom, blood pressure and BBB permeability, microvasculature disruption are compared between acute, chronic hypertensive groups and control group.Cerebral blood flow is tested with laser doppler flowmetry,brain edema is obserbed using micro-MRI multimodal imaging,as well as BBB permeability with real-time florescence imaging. To investigate the role of δPKC playing in tight junction disruption, BBB breakdown and brain edema development. we would elucidate the molecular mechanism involved in HTE and a potentially therapeutic target for prevention of BBB disruption or reduction of cerebrovascular injury would be tested in hypertension-induced encephalopathy in rats. If a similar mechanism occurs in humans, a δPKC inhibitor may be useful for patients at risk of hypertension-induced encephalopathy and stroke.

英文关键词： Magnetic resonance imaging;Hypertensive encephalopathy;Pathogenesis;Blood-brain barrier;Protein kinase C