Development and function of the meninges arachnoid barrier

脑膜蛛网膜屏障的发育和功能

基本信息

批准号：
10620852
负责人：
Julie Siegenthaler
金额：
$ 40.11万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620852
关键词：
Acute Brain Injuries Adult Age Alzheimer&apos s Disease Animal Model Arachnoid mater Award Bacterial Meningitis Behavioral Biological Assay Birth Blood Blood - brain barrier anatomy Blood Vessels Brain Carrier Proteins Cells Central Nervous System Central Nervous System Diseases Cerebrospinal Fluid Choroid Plexus Epithelium Clinical Cognitive deficits Collaborations Data Development Disease Down-Regulation Drug Delivery Systems Dura Mater E-Cadherin Embryo Endothelium Epithelium Equilibrium Functional disorder Future Genetic Transcription Growth Hand Health Homeostasis Immune Impairment Infection Intercellular Junctions Ions Knowledge Life Location Measures Meningeal Meninges Meningitis Mesenchymal Metabolic Methods Modeling Mole the mammal Molecular Motor Movement Multiple Sclerosis Mus Mutant Strains Mice Neonatal Neurodegenerative Disorders Neurons Pathology Patients Perinatal Peripheral Permeability Pharmaceutical Preparations Predisposition Property Proteins Regulation Reporting Role Signal Transduction Site Specific qualifier value Spinal Cord Streptococcal Infections Streptococcus Group B Structure Structure of choroid plexus Subarachnoid Space System Testing Therapeutic Tight Junctions Time Tracer Vascular System Visualization Work age related beta catenin blood cerebrospinal fluid barrier brain tissue cell type central nervous system injury design experimental study fetal immune activation in vivo inhibitor insight interest mouse model neonate nervous system development neuroinflammation neuropathology postnatal postnatal development prenatal protein expression repaired response segregation single-cell RNA sequencing tool

项目摘要

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.

项目概要中枢神经系统（CNS）受到两个屏障系统的保护，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，可以调节可以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于发育至关重要和健康，但会因各种疾病而崩溃，导致或加剧中枢神经系统病理。详细的下中枢神经系统屏障的完好对于有效地将药物输送到大脑和脊髓也至关重要。发展历程脑膜（围绕中枢神经系统的三层结构）水平的 B-CSFB 的功能很差明白了。尽管有证据表明围产期和成人疾病中脑膜存在障碍，免疫细胞激活和进入神经炎症的早期部位。 me-中的两个屏障结构之一 ninges 是蛛网膜屏障层，它将外层脑膜硬脑膜及其非屏障脉管系统分开，来自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屏障细胞规范的机制、层成熟的时间或获得功能特性。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，还没有研究测试不成熟的蛛网膜屏障是否会增加破裂的可能性。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：脑膜开发新工具来研究蛛网膜屏障。这里提出的实验建立在我们最初的基础上发现确定蛛网膜屏障层发育的机制，研究蛛网膜屏障- 的成熟和功能，并测量其对侮辱的反应。为此，我们将：1）利用体内和培养模型来揭示蛛网膜屏障细胞规范的分子机制，2）使用我们的新模型，其中我们在产前干扰蛛网膜屏障的形成，以确定其在建立单独的脑膜免疫中的作用细胞和血管区室以及在母体感染动物模型中保护胎儿大脑 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。完整- 这项工作将极大地推进中枢神经系统屏障系统领域的发展。它将提供第一个模型蛛网膜屏障的发育，包括细胞和分子机制以及出现的时间阻隔性能。它将提供有关蛛网膜屏障功能的重要信息。实验这里建议关注产前大脑，但研究结果将为未来的产后和大脑研究奠定基础。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损伤反应的分析，为未来其他中枢神经系统疾病的研究铺平道路。从长远来看，这些新知识具有潜力用于设计限制分子和细胞在蛛网膜屏障处交叉的新方法以治疗疾病或增加药物治疗的交叉以进入中枢神经系统。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties.

DOI：
10.1523/eneuro.0378-16.2017
发表时间：
2017-05
期刊：
eNeuro
影响因子：
3.4
作者：
Bonney S;Siegenthaler JA
通讯作者：
Siegenthaler JA

Retinoic Acid Is Required for Neural Stem and Progenitor Cell Proliferation in the Adult Hippocampus.

DOI：
10.1016/j.stemcr.2018.04.024
发表时间：
2018-06-05
期刊：
Stem cell reports
影响因子：
5.9
作者：
Mishra S;Kelly KK;Rumian NL;Siegenthaler JA
通讯作者：
Siegenthaler JA

Not just a 'drain': venules sprout brain capillaries.

不仅仅是“引流管”：小静脉会长出脑毛细血管。

DOI：
10.1016/j.tins.2021.08.004
发表时间：
2021
期刊：
Trends in neurosciences
影响因子：
15.9
作者：
Como,ChristinaN;Jones,HannahE;Siegenthaler,JulieA
通讯作者：
Siegenthaler,JulieA

Single-Cell Transcriptomic Analyses of the Developing Meninges Reveal Meningeal Fibroblast Diversity and Function.

DOI：
10.1016/j.devcel.2020.06.009
发表时间：
2020-07-06
期刊：
Developmental cell
影响因子：
11.8
作者：
DeSisto J;O'Rourke R;Jones HE;Pawlikowski B;Malek AD;Bonney S;Guimiot F;Jones KL;Siegenthaler JA
通讯作者：
Siegenthaler JA

Retinoic acid signaling in mouse retina endothelial cells is required for early angiogenic growth.

小鼠视网膜内皮细胞中的视黄酸信号传导是早期血管生成生长所必需的。