Arachnoid barrier breakdown in bacterial meningitis

细菌性脑膜炎中的蛛网膜屏障破坏

• 批准号: 10584456
• 负责人: Julia Derk
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584456
• 关键词: Acute; Address; Adherens Junction; Alzheimer' s Disease; Arachnoid mater; Automobile Driving; Bacteria; Bacterial Meningitis; Behavioral; Binding; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells; Cellular Morphology; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Coculture Techniques; Cognitive deficits; Collaborations; Data; Disease; Down-Regulation; Dura Mater; Endothelial Cells; Epithelial; Exposure to; Fellowship; Functional disorder; Goals; Health; Health system; Homeostasis; Immune; Impairment; In Vitro; Infection; Inflammatory; Knowledge; Leptomeninges; Mediating; Meningeal; Meninges; Meningitis; Mesenchyme; Microbiology; Modeling; Molecular; Motor; Movement; Multiple Sclerosis; Neuraxis; Neurodegenerative Disorders; Neurologic; Pathologic; Pathology; Patients; Peripheral; Phenotype; Predisposition; Property; Proteins; Research Personnel; Site; Spinal Cord; Stimulus; Streptococcal Infections; Streptococcus Group B; Structure; Structure of choroid plexus; Syndrome; System; Techniques; Testing; Tight Junctions; Training; Vimentin; Work; acute infection; blood cerebrospinal fluid barrier; brain endothelial cell; brain health; brain tissue; cytokine; design; epithelial to mesenchymal transition; functional disability; functional loss; in vivo; insight; neonatal bacterial meningitis; nervous system disorder; novel; novel therapeutics; protein metabolite; tool; transcription factor; transcytosis

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.

项目摘要 中枢神经系统（CNS）受两个主要障碍系统保护，即血液脑阻止器（BBB） 以及血经脊髓液屏障（B-CSFB）。这些必需的屏障系统每个都有独特的蜂窝 严格调节可以进入（或退出）大脑和脑脊的分子和细胞的特性 流体（CSF）。中枢神经系统障碍也容易受到各种疾病的崩溃，导致或加剧 中枢神经系统病理学。 B-CSFB在脑膜水平上的崩溃，这是一个周围的三层结构 大脑和脊髓，知之甚少。 脑膜的临界B-CSFB结构是蛛网膜屏障，这是一个紧密的连接，含有上皮 就像将外部脑膜硬脑膜和外围分离的层与内部瘦脑和CSF的外围。与众不同 BBB和B-CSFB的其他部分，关于蛛网膜屏障的敏感性鲜为人知 在疾病期间分解。在这里，我利用B组链球菌（GBS），一种急性细菌性脑膜炎的模型， 为了鉴定蛛网膜屏障分解的细胞和分子机制。我将利用 Siegenthaler实验室（CNS Vasculature和BBB的专家）以及Doran的合并知识 实验室（脑膜炎期间细菌宿主相互作用的领导者），以检验细菌的假设 脑膜炎通过驱动蜗牛1依赖性上皮到间质转变来破坏细胞屏障特性 （EMT），紧密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 如果GBS直接结合原发性蛛网膜屏障细胞，或者GBS是否通过炎症细胞因子发挥其作用。 这项工作的完成将通过提供新工具来大大推动CNS屏障系统的领域 研究蛛网膜屏障功能以及对蛛网膜屏障如何分解的新了解 疾病。我还将生成一个可以是的蛛网膜屏障细胞特性的综合模型 调查了涉及脑膜的其他疾病的细分。关于 蛛网膜屏障有可能被利用，以设计新的方法来限制分子和细胞在 治疗疾病的蛛网膜障碍，并将提供新颖的体外和体内方法来理解 稳态和疾病期间的B-CSFB。最后，这项团契的拟议目标将为我提供 概念，技术和专业培训，需要发展自己为独立研究员 研究中枢神经系统障碍对CNS健康和神经系统疾病的影响。