Neuroprotective mechanisms of CXCL12 in CNS demyelinating diseases

CXCL12在中枢神经系统脱髓鞘疾病中的神经保护机制

基本信息

批准号：
7903346
负责人：
Robyn S Klein
金额：
$ 28.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7903346
关键词：
AMD3100 Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Biological Markers Blood - brain barrier anatomy CNS autoimmune disease CNS autoimmunity CXCL12 gene CXCR4 Receptors CXCR4 gene Cell physiology Cells Clinical Confocal Microscopy Cuprizone Data Demyelinating Diseases Demyelinations Development Disease Encephalomyelitis Endothelial Cells Experimental Autoimmune Encephalomyelitis Exposure to Human Immune In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Injury Kinetics Lead Lesion Leukocytes Mediating Molecular Mononuclear Multiple Sclerosis Mus Myelin Neuraxis Oligodendroglia Pathogenesis Pattern Pericytes Phase Play Process Recovery Role Severities Site Spinal Cord T-Cell Activation TCF Transcription Factor Testing cell motility chemokine in vivo migration novel oligodendrocyte precursor repaired trafficking white matter

AMD3100 Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Biological Markers Blood - brain barrier anatomy CNS autoimmune disease CNS autoimmunity CXCL12 gene CXCR4 Receptors CXCR4 gene Cell physiology Cells Clinical Confocal Microscopy Cuprizone Data Demyelinating Diseases Demyelinations Development Disease Encephalomyelitis Endothelial Cells Experimental Autoimmune Encephalomyelitis Exposure to Human Immune In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Injury Kinetics Lead Lesion Leukocytes Mediating Molecular Mononuclear Multiple Sclerosis Mus Myelin Neuraxis Oligodendroglia Pathogenesis Pattern Pericytes Phase Play Process Recovery Role Severities Site Spinal Cord T-Cell Activation TCF Transcription Factor Testing cell motility chemokine in vivo migration novel oligodendrocyte precursor repaired trafficking white matter

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项目摘要

Project 2: "Neuroprotective mechanisms of CXCL12 during CNS demyelinating diseases" The molecular mechanisms responsible for leukocyte migration and activation within the CNS parenchyma are unknown, as are the mechanisms that orchestrate recovery and myelin repair during remitting phases of both MS and EAE. Blood-brain barrier (BBB) disruption and demyelination are consequences of white matter inflammatory infiltrates22"25. Utilizing confocal microscopy, Dr. Robyn Klein observed the loss of endothelial cell expression of the chemokine CXCL12, normally displays basolateral localization, during CNS autoimmune disease, suggesting CXCL12 plays a role in regulating the blood-brain barrier (BBB). Dr. Klein's team also observed that spinal cord motorneurons express CXCL12 and white matter oligodendrocyte precursors express its receptor CXCR4, suggesting a role for these molecules in remyelination. Thus, a novel, antiinflammatory role for CXCL12 whereby it functions to localize CXCR4-expressing mononuclear cells to the perivascular space, thus limiting their parenchyma! infiltration and activation is proposed in Project 2. Thus, Project 2 will (1) determine how CXCL12-mediated perivascular localization regulates mononuclear cell trafficking during CNS autoimmunity, (2) determine how perivascular localization regulates mononuclear cell activation during CNS autoimmunity, and (3) evaluate how CXCL12 regulates the remyelination process.

项目2：“ CNS脱髓鞘疾病期间CXCL12的神经保护机制” CNS实质内部负责白细胞迁移和激活的分子机制是未知，在两者的汇总期间编排恢复和髓磷脂修复的机制也是如此 MS和EAE。血脑屏障（BBB）破坏和脱髓鞘是白质的后果炎症性浸润22“ 25。利用共聚焦显微镜，Robyn Klein博士观察到内皮细胞的丧失趋化因子CXCL12的表达，通常在CNS自动免疫期间显示基底外侧定位疾病，表明CXCL12在调节血脑屏障（BBB）中起作用。克莱因博士的团队观察到脊髓动神经元表达CXCL12和白质少突胶质前体表达其受体CXCR4，这表明这些分子在再生中的作用。因此，一种新颖的抗炎作用 CXCL12的作用，其功能可以将表达CXCR4的单核细胞定位到血管周空间，因此限制了他们的实质！在项目2中提出了浸润和激活。因此，项目2将（1）确定CXCL12介导的周围定位如何调节单核细胞中枢神经系统自身免疫性期间的贩运，（2）确定血管周期定位如何调节单核细胞 CNS自身免疫性期间的激活，（3）评估CXCL12如何调节再生过程。