Development and function the meninges arachnoid barrier

脑膜蛛网膜屏障的发育和功能

• 批准号: 10355920
• 负责人: Julie Siegenthaler
• 金额: $ 43.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355920
• 关键词: Acute Brain Injuries; Affect; Alzheimer' s Disease; Animal Model; Arachnoid mater; Award; Bacterial Infections; Bacterial Meningitis; Behavioral; Birth; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrovascular system; Cognitive deficits; Coin; Collaborations; Data; Development; Disease; Dura Mater; E-Cadherin; Embryo; Epithelial; Epithelial Cells; Equilibrium; Excision; Failure; Fibroblasts; Genetic Transcription; Health; Health system; Homeostasis; Immune; Infection; Inflammation; Ions; Knowledge; Leptomeninges; Maintenance; Measures; Meningeal; Meningeal lymphatic system; Meninges; Meningitis; Mesenchymal; Modeling; Molecular; Motor; Movement; Mus; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Play; Predisposition; Property; Proteins; Regulation; Repression; Role; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Spinal Cord; Structure; Structure of choroid plexus; Subarachnoid Space; System; Techniques; Testing; Tight Junctions; Tracer; Vascular System; Work; beta catenin; blood cerebrospinal fluid barrier; blood vessel development; brain health; brain tissue; design; experimental study; gain of function; in vivo; inhibitor/antagonist; insight; lymphatic vessel; mouse model; nervous system development; neuroinflammation; programs; protein metabolite; repaired; response; tool; trafficking; wasting

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 essential for development and health but are vulnerable to breakdown in a variety of diseases, causing or exacerbating CNS pathology. CNS barriers are also an impediment to delivery of therapies to treat disease. The development and function of the B-CSFB at the level of the meninges, a trilayered structure that surrounds the brain and spinal cord, is poorly understood. This is despite evidence implicating the meninges as an early site of immune cell entry into the CNS in neuroinflammatory diseases and the growing recognition of brain waste removal systems where waste must traverse the B-CSFB before removal via the meningeal lymphatics. One of two barrier structures in the meninges is the arachnoid barrier, a tight junction containing epithelial- like layer that segregates the outer meningeal dura, which contains non-barrier blood vasculature, from CSF in the subarachnoid space. Unlike the BBB and other parts of the B-CSFB, there is nothing known about the developmental program underlying arachnoid barrier formation. Further, only a few studies have looked at arachnoid barrier function and breakdown in CNS diseases, the conclusions of which were limited to descriptive studies. We have combined our knowledge of CNS vascular and BBB development with our unique expertise in the meninges to develop several new tools to study arachnoid barrier development and function. We will apply these new tools to study an animal model of a disease with high relevance to the meninges and the arachnoid barrier, bacterial meningitis. Experiments proposed here will identify mechanisms that underlie arachnoid barrier cell development and maintenance, investigate arachnoid barrier function, and measure its response to insult. To do this we will: 1) utilize in vivo and culture models to uncover the cellular and molecular mechanisms of arachnoid barrier specification and maturation, 2) use our new model where we perturb arachnoid barrier formation to determine its role in establishing separate meningeal and immune and vascular compartments 3) identify the cellular and molecular mechanisms of arachnoid barrier breakdown in bacterial meningitis. Completion of this work will substantially advance the field of CNS barrier systems by providing new tools to study arachnoid barrier function. We will 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 or increase crossing of drugs as a means to access the CNS.

项目概要 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）。这些重要的屏障系统各自具有独特的细胞 严格调节可以进入（或退出）大脑和脑脊髓的分子和细胞的特性 液体（脑脊液）。中枢神经系统障碍对于发展和健康至关重要，但很容易因各种原因而崩溃 疾病，引起或加剧中枢神经系统病理。中枢神经系统障碍也是传递的障碍 治疗疾病的疗法。 B-CSFB 在脑膜水平的发育和功能，是一个三层结构 人们对大脑和脊髓周围的结构知之甚少。尽管有证据表明 脑膜是神经炎症性疾病和日益增长的免疫细胞进入中枢神经系统的早期部位 认可脑废物清除系统，其中废物必须先经过 B-CSFB，然后才能通过 脑膜淋巴管。 脑膜中的两个屏障结构之一是蛛网膜屏障，这是一种包含上皮细胞的紧密连接 将包含无屏障血管系统的外脑膜硬脑膜与脑脊液隔离开来的类似层 蛛网膜下腔。与 BBB 和 B-CSFB 的其他部分不同，对于 蛛网膜屏障形成的发育程序。此外，只有少数研究关注 中枢神经系统疾病中的蛛网膜屏障功能和破坏，其结论仅限于描述性 研究。 我们将中枢神经系统血管和 BBB 开发的知识与我们在以下领域的独特专业知识相结合： 脑膜开发几种新工具来研究蛛网膜屏障的发育和功能。我们将应用这些 研究与脑膜和蛛网膜屏障高度相关的疾病动物模型的新工具， 细菌性脑膜炎。这里提出的实验将确定蛛网膜屏障细胞的机制 发育和维护，研究蛛网膜屏障功能，并测量其对侮辱的反应。要做的事 我们将：1）利用体内和培养模型来揭示蛛网膜的细胞和分子机制 屏障规范和成熟，2）使用我们的新模型，我们扰乱蛛网膜屏障的形成 确定其在建立单独的脑膜、免疫和血管区室中的作用 3) 确定 细菌性脑膜炎中蛛网膜屏障破坏的细胞和分子机制。完成此 这项工作将通过提供研究蛛网膜屏障的新工具，极大地推进中枢神经系统屏障系统领域的发展 功能。我们将生成一个蛛网膜屏障细胞特性的综合模型，可以 研究了涉及脑膜的其他疾病的分解情况。这些新知识关于 蛛网膜屏障有潜力被用来设计新的方法来限制分子和细胞的交叉 蛛网膜屏障以治疗疾病或增加药物的交叉作为进入中枢神经系统的手段。