Development and function the meninges arachnoid barrier

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)。中枢神经系统障碍对发展和健康是必不可少的，但很容易以各种形式被打破 疾病，引起或加重中枢神经系统的病理。中枢神经系统障碍也是交付的障碍 治疗疾病的疗法。B-CSFB在脑膜水平的发育和功能 围绕大脑和脊髓的结构，人们知之甚少。尽管有证据表明 脑膜作为免疫细胞进入中枢神经系统的早期部位在神经炎性疾病和生长中 识别大脑废物清除系统，其中废物必须通过B-CSFB在通过 脑膜淋巴管。 脑膜的两种屏障结构之一是蛛网膜屏障，这是一个包含上皮细胞的紧密连接。 类似的一层，将包含非屏障血管的外部脑膜硬脑膜与脑脊液隔开 蛛网膜下腔。与BBB和B-CSFB的其他部分不同，人们对 蛛网膜屏障形成的潜在发育程序。此外，只有几项研究关注过 中枢神经系统疾病的蛛网膜屏障功能和破坏，其结论仅限于描述性 学习。 我们将我们在中枢神经系统血管和血脑屏障发育方面的知识与我们在 脑膜开发几种新的工具来研究蛛网膜屏障的发育和功能。我们将应用这些 研究一种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背后的机制 开发和维护，调查蛛网膜屏障功能，并测量其对侮辱的反应。去做 为此，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，其中我们扰动蛛网膜屏障的形成以 确定其在建立分离的脑膜、免疫和血管隔间中的作用3)确定 细菌性脑膜炎蛛网膜屏障破坏的细胞和分子机制。完成这项工作 这项工作将为研究蛛网膜屏障提供新的工具，从而大大推进中枢神经系统屏障领域的发展 功能。我们将生成蛛网膜屏障细胞属性的综合模型，该模型可以 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或增加药物的交叉，以此作为进入中枢神经系统的手段。

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.