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

基本信息

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
项目类别：
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

项目摘要

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.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供该子项目的主要支持。并且子项目的主要研究者可能是由其他来源提供的，包括其他 NIH 来源的子项目可能列出的总成本。代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。猿猴免疫缺陷病毒 (SIV) 对血脑屏障通透性的影响可能是由神经胶质细胞对中枢神经系统中存在的病毒的反应引发的，这种对病毒的局部炎症反应通过 RNA 调节和蛋白质磷酸化驱动内皮细胞的失调。我们确定了 CD263 的新下调，CD263 是 SIV 刺激的内皮细胞中的一种 TNF 诱饵受体，通常用于减轻 TRAIL 的破坏作用。内皮细胞遇到促炎刺激，来自 SIVmac251 感染的巨噬细胞的上清液足以导致星形胶质细胞过度产生 TNF-¿此外，相同的上清液使内皮细胞中 CCL2 和 CXCL8 的产生增加约 4 倍。内皮细胞中的受体通过其配体激活 NF¿ B 在内皮细胞中，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。