Arachnoid barrier breakdown in bacterial meningitis

项目摘要 中枢神经系统受到两个主要屏障系统的保护，即血脑屏障(Bbb)。 血脑脊液屏障(B-CSFB)。这些基本屏障系统每个都有独特的细胞 对进入(或退出)大脑和脑脊髓的分子和细胞进行严格调控的特性 液体(脑脊液)。中枢神经系统屏障也容易在各种疾病中崩溃，导致或加剧 中枢神经系统病理学。B-CSFB在脑膜水平的分解，脑膜是围绕在周围的三层结构 大脑和脊髓，人们对此知之甚少。 脑膜的关键B-CSFB结构是蛛网膜屏障，这是一个紧密的连接，包含上皮细胞和 类似于将外硬脑膜和外周脑膜与内脑膜和脑脊液隔开的一层。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，我利用了B组链球菌(GBS)，一种急性细菌性脑膜炎的模型， 以确定蛛网膜屏障破坏的细胞和分子机制。我将利用 西根塔勒实验室(CNS血管和血脑屏障方面的专家)和杜兰的综合知识 LAB(研究脑膜炎期间细菌-宿主相互作用的领先者)，以验证细菌 脑膜炎通过驱动依赖Snail1的上皮细胞向间充质细胞的转变破坏细胞屏障特性 (EMT)，紧密和粘连连接的丧失，以及功能障碍的完整性受损。此外，我会澄清 如果GBS直接结合原发蛛网膜屏障细胞，或者GBS通过炎性细胞因子发挥作用。 这项工作的完成将通过提供新的工具大大推进中枢神经系统屏障系统领域的发展 目的：研究蛛网膜下腔屏障的功能，并对蛛网膜下腔屏障如何被破坏有新的认识。 疾病。我还将生成一个蛛网膜屏障细胞特性的综合模型，它可以 调查涉及脑膜的其他疾病的分解情况。这一新的关于 蛛网膜屏障有可能被利用来设计新的方法来限制分子和细胞在 蛛网膜屏障用于治疗疾病，并将提供新的体外和体内理解方法 B-CSFB在动态平衡和疾病中的变化。最后，这个奖学金提出的目标将给我 作为一名独立研究人员的发展所必需的概念、技术和专业培训 研究中枢神经系统障碍对中枢神经系统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.