Controlling blood-brain barrier integrity in the ischemic brain by modulating gatekeepers at the abluminal endothelial membrane

通过调节近腔内皮膜的看门人来控制缺血大脑中血脑屏障的完整性

• 批准号: 123514717
• 负责人: Professor Dr. Dirk M. Hermann
• 金额: --
• 依托单位: Lehrstuhl für Vaskuläre Neurologie, Demenz
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/123514717?language=en
• 关键词: Controlling; blood; brain; barrier; integrity

Apolipoprotein-E (ApoE), a major risk factor of ischemic stroke, has recently been shown to control tight junction integrity and ATP-binding cassette (ABC) transporter abundance at the ischemic blood-brain barrier (BBB). ApoE acts via low density lipoprotein (LDL) receptor-related proteins (LRP), which are found on endothelial cells and pericytes, the precise contribution of both being still debated. In this proposal, we would like to evaluate the role of different LRPs (LRP1, LRP5/6, LRP8), their associated proteins (i.e., Frizzled) and downstream signals (e.g., JNK1/2/ c-Jun, GSK3beta/ beta-catenin, FAK, RhoA) in controlling (a) the expression and interaction of tight junctions, (b) the expression and cellular localization of ABC transporters on brain capillaries and (c) the distribution of drugs between the blood and brain after middle cerebral artery occlusion. Effects of the only existing stroke therapeutic, recombinant tissue-plasminogen activator (tPA), on neurovascular signaling will be evaluated and the action of a potential therapeutic in Alzheimer's disease, the gamma-secretase inhibitor LY450139, will be assessed, searching for strategies that might allow to circumvent deleterious effects of tPA on ischemic blood vessels. By exposing pericyte deficient mice to middle cerebral artery occlusion, we will dissect endothelial and pericytic responses to ApoE, examining the role of the JNK1/2/ c-Jun and cyclophilin-A/ nuclear factor-kappaB/ matrix-metalloproteinase-9 pathways in maintaining post-ischemic BBB integrity. With our studies we would like to develop a more thorough understanding of the abluminal endothelial membrane as a signal interface, aiming to identify targets via which neurovascular integrity and the efficacy of stroke therapeutics might be improved.

载脂蛋白-E (ApoE) 是缺血性中风的主要危险因素，最近被证明可以控制缺血性血脑屏障 (BBB) 处的紧密连接完整性和 ATP 结合盒 (ABC) 转运蛋白丰度。 ApoE 通过低密度脂蛋白 (LDL) 受体相关蛋白 (LRP) 发挥作用，这些蛋白在内皮细胞和周细胞上发现，两者的确切作用仍存在争议。在本提案中，我们希望评估不同 LRP（LRP1、LRP5/6、LRP8）、其相关蛋白（即 Frizzled）和下游信号（例如 JNK1/2/ c-Jun、GSK3beta/ beta-）的作用。连环蛋白、FAK、RhoA) 控制 (a) 紧密连接的表达和相互作用，(b) ABC 转运蛋白在脑毛细血管上的表达和细胞定位，以及(c)大脑中动脉闭塞后药物在血液和大脑之间的分布。将评估唯一现有的中风治疗药物重组组织纤溶酶原激活剂 (tPA) 对神经血管信号传导的影响，并将评估阿尔茨海默氏病的潜在治疗药物 γ 分泌酶抑制剂 LY450139 的作用，寻找可能的策略可以避免 tPA 对缺血血管的有害影响。通过将周细胞缺陷小鼠暴露于大脑中动脉闭塞，我们将剖析内皮细胞和周细胞对 ApoE 的反应，检查 JNK1/2/c-Jun 和亲环蛋白-A/核因子-kappaB/基质金属蛋白酶-9 通路在维持缺血后血脑屏障的完整性。通过我们的研究，我们希望对作为信号接口的近腔内皮膜有更全面的了解，旨在确定可以改善神经血管完整性和中风治疗效果的靶标。