Arachnoid barrier breakdown in bacterial meningitis

项目摘要 中枢神经系统（CNS）受到两个主要屏障系统的保护，即血脑屏障（BBB）。 和血-脑脊液屏障（B-CSFB）。这些基本屏障系统各自具有独特的细胞 严格调节进入（或离开）大脑和脑脊液的分子和细胞的特性 脑脊液（CSF）。CNS屏障也容易在各种疾病中被破坏，引起或加重 CNS病理学。B-CSFB在脑膜水平的击穿，脑膜是一种三层结构， 对大脑和脊髓的了解很少。 脑膜的关键B-CSFB结构是蛛网膜屏障，一种包含上皮细胞的紧密连接， 类似于将外部脑膜硬脑膜和外周与内部软脑膜和CSF隔离的层。不像 BBB和B-CSFB的其他部分，关于蛛网膜屏障的易感性知之甚少 在疾病期间崩溃。在这里，我利用B族链球菌（GBS），一种急性细菌性脑膜炎模型， 以确定蛛网膜屏障破坏的细胞和分子机制。我会利用 结合Siegenthaler实验室（CNS脉管系统和BBB专家）以及Doran 实验室（研究脑膜炎期间细菌-宿主相互作用的领导者），以检验细菌 脑膜炎通过驱动Snail 1依赖性上皮细胞向间质细胞转化破坏细胞屏障特性 (EMT)紧密连接和粘附连接的丧失以及功能屏障完整性受损。此外，我将阐明 GBS是否直接结合初级蛛网膜屏障细胞或GBS是否通过炎性细胞因子发挥其作用。 这项工作的完成将通过提供新的工具大大推进CNS屏障系统领域 研究蛛网膜屏障功能，并对蛛网膜屏障如何在脑内破裂有新的认识。 疾病我还将生成一个蛛网膜屏障细胞特性的综合模型， 研究其他涉及脑膜的疾病的分解。这些新知识 蛛网膜屏障有可能被开发用于设计新的方法来限制分子和细胞的交叉， 并将提供新的体外和体内方法， B-CSFB在体内平衡和疾病。最后，这个奖学金的拟议目标将给我 概念，技术和专业培训，以发展自己作为一个独立的研究人员 研究CNS屏障对CNS健康和神经系统疾病的影响。

Project Summary The central nervous system (CNS) is protected by two major barrier systems, the blood brain-barrier (BBB) and the blood-cerebrospinal fluid barrier (B-CSFB). These essential barrier systems each have unique cellular properties that tightly regulate the molecules and cells that can enter (or exit) the brain and the cerebrospinal fluid (CSF). CNS barriers are also vulnerable to breakdown in a variety of diseases, causing or exacerbating CNS pathology. The breakdown of the B-CSFB at the level of the meninges, a trilayered structure that surrounds the brain and spinal cord, is poorly understood. The critical B-CSFB structures of the meninges is the arachnoid barrier, a tight junction containing epithelial- like layer that segregates the outer meningeal dura and periphery from the inner leptomeninges and CSF. Unlike the BBB and other parts of the B-CSFB, there is very little known about the susceptibility of the arachnoid barrier to breakdown during disease. Here, I utilize Group B Streptococcus (GBS), a model of acute bacterial meningitis, in order to identify the cellular and molecular mechanisms of arachnoid barrier breakdown. I will leverage the combined knowledge of the Siegenthaler lab (experts in CNS vasculature and the BBB) as well as the Doran Lab (leaders in studying bacteria-host interactions during meningitis) in order to test the hypothesis that bacterial meningitis disrupts cellular barrier properties by driving Snail1-dependent Epithelial to Mesenchyme Transition (EMT), loss of tight and adherens junctions, and impaired functional barrier integrity. Furthermore, I will elucidate if GBS directly binds primary arachnoid barrier cells or if GBS exerts its effects through inflammatory cytokines. Completion of this work will substantially advance the field of CNS barrier systems by providing new tools to study arachnoid barrier function and a novel understanding of how the arachnoid barrier breaks down in disease. I will also generate a comprehensive model of arachnoid barrier cellular properties that can be investigated for breakdown in other diseases that involve the meninges. This new knowledge about the arachnoid barrier has the potential to be exploited to design new ways to limit crossing of molecules and cells at the arachnoid barrier to treat disease and will provide novel in vitro and in vivo approaches for understanding the B-CSFB during homeostasis and disease. Finally, the proposed goals of this fellowship will give me the conceptual, technical, and professional training necessary to develop myself as an independent researcher investigating the impact of CNS barriers on CNS health and neurological diseases.