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屏障对于发育和健康是必不可少的，但在各种情况下容易被破坏。 引起或加重CNS病理的疾病。CNS屏障也是递送药物的障碍。 治疗疾病的方法。B-CSFB在脑膜水平的发育和功能， 围绕大脑和脊髓的结构，知之甚少。尽管有证据表明， 脑膜是神经炎性疾病中免疫细胞进入CNS的早期部位， 识别脑废物清除系统，其中废物必须在通过B-CSFB清除之前穿过B-CSFB 脑膜炎 脑膜中的两种屏障结构之一是蛛网膜屏障，它是一种紧密连接，包含上皮细胞和神经细胞。 类似于将包含非屏障血管系统的外脑膜硬脑膜与CSF隔离的层， 蛛网膜下腔与BBB和B-CSFB的其他部分不同， 蛛网膜屏障形成的发育程序。此外，只有少数研究关注 蛛网膜屏障功能和CNS疾病的破坏，其结论仅限于描述性的 问题研究 我们将CNS血管和BBB发育的知识与我们在以下方面的独特专业知识相结合： 脑膜开发几个新的工具来研究蛛网膜屏障的发展和功能。我们将应用这些 研究与脑膜和蛛网膜屏障高度相关疾病的动物模型的新工具， 细菌性脑膜炎本实验将确定蛛网膜屏障细胞的机制， 发育和维持，研究蛛网膜屏障功能，并测量其对损伤的反应。做 我们将：1）利用体内和培养模型来揭示蛛网膜炎的细胞和分子机制， 屏障规范和成熟，2）使用我们的新模型，我们扰动蛛网膜屏障形成， 确定其在建立单独的脑膜、免疫和血管隔室中的作用; 3）确定 细菌性脑膜炎蛛网膜屏障破坏的细胞和分子机制。完成本 通过提供研究蛛网膜屏障的新工具，这项工作将大大推进中枢神经系统屏障系统领域的研究 功能我们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， 蛛网膜屏障以治疗疾病或增加药物的交叉作为进入CNS的手段。