Leukotrienes and blood-brain barrier

白三烯和血脑屏障

基本信息

批准号：
8451256
负责人：
Kwang S Kim
金额：
$ 38.15万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451256
关键词：
Actins Adherens Junction Affect Allergic Disease Arachidonate 5-Lipoxygenase Blood Blood - brain barrier anatomy Blood capillaries Brain Breathing Cardiovascular Diseases Cell physiology Cells Central Nervous System Infections Cerebrum Collagen Cryptococcus neoformans Cytoskeleton Cytosolic Phospholipase A2 DNA Sequence Rearrangement Development Electrical Resistance Endothelial Cells Escherichia coli Exhibits Experimental Animal Model Family Fungemia Gene Deletion Human In Vitro Lead Leukotrienes Life Lung diseases Meningitis Meningoencephalitis Modeling Organ Organism Penetration Permeability Pinocytosis Property Protein Kinase C Protein-Serine-Threonine Kinases Proteins Regulation Resources Role Sepsis Signal Transduction Signal Transduction Pathway Signaling Molecule Tight Junctions Time base capillary cysteinyl-leukotriene innovation microbial microorganism monolayer novel pathogen prevent public health relevance receptor relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): Microbial traversal of the blood-brain barrier is required for the development of central nervous system infection, but the underlying mechanisms remain incompletely understood. The blood-brain barrier is a structural and functional barrier that is formed by brain microvascular endothelial cells and protects the brain from any microorganisms circulating in the blood, but recent studies have shown that meningitis-causing pathogens are able to cross the blood-brain barrier as live organisms. We have developed the in vitro blood-brain barrier model by isolation and cultivation of human brain microvascular endothelial cells (HBMEC). Upon cultivation on collagen-coated Transwell inserts the HBMEC monolayers exhibit morphological and functional properties of tight junction formation and polar monolayer. Our Preliminary Studies revealed that meningitis-causing pathogens traverse the HBMEC monolayers without affecting the HBMEC integrity, as assessed by transendothelial electrical resistance and permeability, and microbial traversal of the HBMEC monolayers involves specific host signal transduction pathways. Our additional Preliminary Studies using pharmacological inhibition and gene deletion suggest for the first time that host 5-lipoxygenase is likely to be involved in microbial traversal of the blood-brain barrier. Leukotrienes are synthesized by 5-lipoxygenase and shown to have pathophysiological roles in respiratory diseases, allergic diseases and cardiovascular diseases, but their role in microbial traversal of the blood-brain barrier has not been explored. Our Preliminary Studies with the receptor antagonists revealed that cysteinyl leukotrienes are likely to be involved in microbial traversal of the blood-brain barrier. The overall aim of this application is to investigate and characterize the host signaling molecules involved in microbial traversal of the blood- brain barrier. The information derived from this application will demonstrate the novel contributions of 5- lipoxygenase and leukotrienes to microbial traversal of the blood-brain barrier.

描述（由申请人提供）：中枢神经系统感染的发生需要微生物穿过血脑屏障，但其潜在机制仍不完全清楚。血脑屏障是由大脑微血管内皮细胞形成的结构和功能屏障，可保护大脑免受血液中循环的任何微生物的侵害，但最近的研究表明，引起脑膜炎的病原体能够穿过血脑屏障作为活的有机体。我们通过分离培养人脑微血管内皮细胞（HBMEC），建立了体外血脑屏障模型。在胶原蛋白包被的 Transwell 插入物上培养后，HBMEC 单层表现出紧密连接形成和极性单层的形态和功能特性。我们的初步研究表明，通过跨内皮电阻和渗透性评估，引起脑膜炎的病原体穿过 HBMEC 单层而不影响 HBMEC 完整性，并且微生物穿过 HBMEC 单层涉及特定的宿主信号转导途径。我们使用药理学抑制和基因删除进行的额外初步研究首次表明宿主 5-脂氧合酶可能参与微生物穿过血脑屏障。白三烯由5-脂氧合酶合成，在呼吸系统疾病、过敏性疾病和心血管疾病中具有病理生理作用，但其在微生物穿过血脑屏障中的作用尚未被探索。我们对受体拮抗剂的初步研究表明，半胱氨酰白三烯可能参与微生物穿过血脑屏障。该应用的总体目标是研究和表征参与微生物穿越血脑屏障的宿主信号分子。从该应用中获得的信息将证明 5-脂氧合酶和白三烯对微生物穿过血脑屏障的新贡献。