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.

项目摘要中枢神经系统（CNS）受两个屏障系统保护，血液脑阻止器（BBB）和血脊髓流体屏障（B-CSFB）。这些障碍系统具有独特的蜂窝性能来调节可以进入或退出CNS和CSF的分子和细胞。中枢神经系统障碍对于开发至关重要和健康，但各种疾病的细分，导致或加剧了CNS病理学。详细的不足中枢神经系统屏障的站立对于有效地输送到大脑和脊髓的药物也是必不可少的。发展 B-CSFB在脑膜水平上的功能，围绕CNS的三层结构很差理解。尽管有证据表明围产期和成人疾病中脑膜上的障碍物是免疫细胞激活和神经炎症中进入的早期部位。 Me-中的两个障碍结构之一 Ninges是蛛网屏障层，它隔离了外部脑膜硬脑膜及其非级脉管脉管系统从蛛网膜下腔中的CSF和细胞类型。与BBB和B-CSFB的其他部分不同，什么也没有关于蛛网膜屏障细胞规范的机制，层成熟的时间或采集的机制已知功能性能。此外，只有少数研究研究了中枢神经系统疾病中的蛛网膜屏障功能障碍到目前为止，尚未测试未成熟的蛛网膜障碍是否增加了崩溃的脆弱性。我们已经将对中枢神经系统血管和BBB开发的知识与我们的独特专业知识相结合措施开发新工具来研究蛛网障碍。这里提出的实验基于我们的最初发现识别蛛网膜屏障层发育的机制，研究蛛网膜条成熟和功能越来越大，并在侮辱中衡量其反应。为此，我们将：1）利用体内和文化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，其中我们在产前扰动蛛网膜屏障形成，以确定其在建立单独脑膜免疫的作用细胞和血管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分解的细胞和分子机制。组成这项工作的作用将大大推动CNS屏障系统的领域。它将提供第一个模型蛛网膜屏障的发展，包括细胞和分子机制以及出现的时机屏障特性。它将提供有关蛛网膜屏障功能的重要信息。实验此处提出的重点是产前大脑成人功能。第三，它将提供对CNS损害的蛛网膜障碍响应日期的最详细分析，为其他中枢神经系统疾病的未来研究铺平道路。从长远来看，这种新知识具有潜力用于设计新方法来限制分子和细胞在蛛网膜障碍处的交叉以治疗疾病或增加药物治疗剂进入中枢神经系统的穿越。

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

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。

DOI：
10.1016/j.diff.2022.12.002
发表时间：
2023
期刊：
Differentiation; research in biological diversity
影响因子：
0
作者：
Como,ChristinaN;Cervantes,Cesar;Pawlikowski,Brad;Siegenthaler,Julie
通讯作者：
Siegenthaler,Julie

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