Development and function of the meninges arachnoid barrier

项目摘要 中枢神经系统(CNS)由两个屏障系统保护，即血脑屏障(BBB)和 血脑脊液屏障(B-CSFB)。这些屏障系统具有独特的细胞特性，可以调节 能够进入或离开中枢神经系统和脑脊液的分子和细胞。中枢神经系统障碍对发展至关重要 和健康，但在各种疾病中崩溃，导致或加剧中枢神经系统的病理。一份详细的- 中枢神经系统屏障的竖立对于有效地将药物输送到大脑和脊髓也是至关重要的。最新进展 B-CSFB在脑膜水平的功能很差，B-CSFB是围绕中枢神经系统的三层结构 明白了。尽管有证据表明脑膜定位障碍在围产期和成人疾病中的作用 神经炎症中免疫细胞激活和进入的早期部位。Me中的两个屏障结构之一- 硬脑膜是蛛网膜屏障，它将外硬脑膜及其非屏障血管隔开， 从脑脊液和蛛网膜下腔的细胞类型。与BBB和B-CSFB的其他部分不同，没有什么 已知蛛网膜下腔屏障细胞规范的机制，层成熟或获取 功能属性。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障碍。 到目前为止，还没有研究测试未成熟的蛛网膜屏障是否增加了崩溃的易感性。 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 脑膜开发研究蛛网膜屏障的新工具。这里提出的实验建立在我们最初的 发现蛛网膜下腔屏障层发育的机制，研究蛛网膜层 更多的成熟和功能，并测量其在侮辱中的反应。为此，我们将：1)利用体内和培养 用于揭示蛛网膜屏障细胞规范的分子机制的模型，2)使用我们的新模型 我们在产前干扰蛛网膜屏障的形成，以确定其在建立分离脑膜免疫中的作用。 在母体感染的动物模型中，细胞和血管间隔以及对胎儿大脑的保护作用3) 确定细菌性脑膜炎蛛网膜屏障破坏的细胞和分子机制。完全- 这项工作的开展将极大地推动CNS屏障系统领域的发展。它将提供第一个型号的 蛛网膜屏障的发育，包括细胞和分子机制以及出现的时间 屏障属性。它将提供有关蛛网膜屏障功能的重要信息。实验 这里提出的重点是产前大脑，但研究结果将为未来在出生后和 成人功能。第三，它将提供迄今为止最详细的蛛网膜屏障对中枢神经系统侮辱的反应， 为今后研究其他中枢神经系统疾病铺平道路。从长远来看，这种新知识有潜力 用来设计新的方法来限制分子和细胞在蛛网膜屏障上的交叉来治疗疾病 或增加药物治疗的交叉，以访问中枢神经系统。

Project Summary The central nervous system (CNS) is protected by two barrier systems, the blood brain-barrier (BBB) and the blood-cerebrospinal fluid barrier (B-CSFB). These barrier systems have unique cellular properties that regulate the molecules and cells that can enter or exit the CNS and the CSF. CNS barriers are essential for development and health but breakdown in a variety of diseases, causing or exacerbating CNS pathology. A detailed under- standing of CNS barriers is also essential for efficient drug delivery to the brain and spinal cord. The development and function of the B-CSFB at the level of the meninges, a trilayered structure that surrounds the CNS, is poorly understood. This is despite evidence implicating meninges-located barriers in perinatal and adult diseases as an early site of immune cell activation and entry in neuroinflammation. One of two barrier structures in the me- ninges is the arachnoid barrier layer, which segregates the outer meningeal dura and its non-barrier vasculature, from the CSF and cell types in the subarachnoid space. Unlike the BBB and other parts of the B-CSFB, nothing is known about mechanisms of arachnoid barrier cell specification, timing of layer maturation or acquisition of functional properties. Further, only a few studies have looked at arachnoid barrier dysfunction in CNS diseases and so far, no studies have tested if an immature arachnoid barrier has enhanced vulnerability to breakdown. We have combined our knowledge of CNS vascular and BBB development with our unique expertise in the meninges to develop new tools to study the arachnoid barrier. Experiments proposed here build upon our initial discoveries to identify mechanisms that underlie arachnoid barrier layer development, investigate arachnoid bar- rier maturation and function, and measure its response in insult. To do this we will: 1) utilize in vivo and culture models to uncover the molecular mechanisms of arachnoid barrier cell specification, 2) use our new model where we perturb arachnoid barrier formation prenatally to determine its role in establishing separate meninges immune cell and vascular compartments and in protecting the fetal brain in an animal model of maternal infection 3) identify the cellular and molecular mechanisms of arachnoid barrier breakdown in bacterial meningitis. Comple- tion of this work will substantially advance the field of CNS barrier systems. It will provide the first model of arachnoid barrier development including the cellular and molecular mechanisms and the timing of emergence of barrier properties. It will provide important information about the function of the arachnoid barrier. Experiments proposed here focus on the prenatal brain however findings will set the stage for future studies in postnatal and adult function. Third, it will provide the most detailed analysis to date of arachnoid barrier response to CNS insult, paving the way for future studies in other CNS diseases. In the long term, this new knowledge has the potential to be used to design new ways to limit crossing of molecules and cells at the arachnoid barrier to treat disease or increase crossing of drug therapeutics to access the CNS.