DYMANICS OF ENDOTHELIAL CELL SIGNALING AND SIVE NEUROINFLAMMATION

内皮细胞信号传导和严重神经炎症的动力学

• 批准号: 8358124
• 负责人: ANDREW G MACLEAN
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358124
• 关键词: Actins; Astrocytes; Blood - brain barrier anatomy; CCL2 gene; Cytoskeletal Modeling; Down-Regulation; Endothelial Cells; Endothelium; Funding; Grant; IL8 gene; Inflammatory; Ligands; MYLK gene; National Center for Research Resources; Neuraxis; Permeability; Phosphorylation; Primates; Principal Investigator; Production; RNA; Reaction; Research; Research Infrastructure; Resources; SIV; Signal Transduction; Source; Stimulus; TNF gene; TNFSF10 gene; Tumor Necrosis Factor Receptor; United States National Institutes of Health; Up-Regulation; Virus; cost; macrophage; neuroinflammation; novel; receptor; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The effects of simian immunodeficiency virus (SIV) on blood-brain barrier permeability are likely initiated by glial response to the presence of virus in the central nervous system. This localized inflammatory reaction to the virus drives dysregulation of the endothelium by RNA modulation and protein phosphorylation. We determined a novel downregulation of CD263, a TNF decoy receptor in SIV stimulated endothelial cells, that normally serves to mitigate the damaging effects of TRAIL when the endothelium encounters proinflammatory stimuli. Supernatant from SIVmac251 infected macrophage was sufficient to cause astrocytes to overproduce TNF-¿ by about 4-fold. Further, the same supernatant increased CCL2 and CXCL8 production in endothelial cells. The activation of the TNF-¿ receptor in endothelial cells by its ligand causes activation of NF¿B in the endothelium. This leads to the subsequent upregulation/phosphorylation of MLCK, actin cytoskeletal reorganization, and redistribution of ZO-1.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 猴免疫缺陷病毒（SIV）对血脑屏障通透性的影响可能是由神经胶质细胞对病毒存在的中枢神经系统反应启动的。这种对病毒的局部炎症反应通过RNA调节和蛋白磷酸化驱动内皮的失调。我们确定了一种新的下调CD 263，TNF诱饵受体在SIV刺激的内皮细胞，通常用于减轻损伤作用的TRAIL时，内皮细胞遇到促炎刺激。来自SIVmac 251感染的巨噬细胞的上清液足以导致星形胶质细胞过量产生TNF-α约4倍。此外，相同的上清液增加了内皮细胞中CCL 2和CXCL 8的产生。内皮细胞中的TNF-α受体被其配体激活，导致内皮细胞中的NF-β B激活。这导致随后MLCK的上调/磷酸化、肌动蛋白细胞骨架重组和ZO-1的重新分布。