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

点击翻译按钮获取中文摘要

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.