CNS inflammation in nervous and mental disease

神经和精神疾病中的中枢神经系统炎症

基本信息

批准号：
7900468
负责人：
Joel S Pachter
金额：
$ 36.91万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900468
关键词：
Active Immunization Adhesions Animal Model Animals Astrocytes Blood Blood - brain barrier anatomy Blood Circulation Brain C57BL/6 Mouse CCL2 gene Caveolae Cells Central Nervous System Diseases Clinical Communication Comprehension Cytoplasm Disease Encephalomyelitis Endothelial Cells Experimental Autoimmune Encephalomyelitis Extravasation Foundations Funding Future Gene Deletion Glycocalyx Grant Immunoelectron Microscopy Inflammation Inflammatory Invaded Knock-out Knockout Mice Laboratories Left Leukocytes Microglia Monocyte Chemoattractant Protein-1 Mononuclear Leukocytes Movement Multiple Sclerosis Mus Nervous system structure Neuraxis Neurons Pathogenesis Pathway interactions Peptides Phenotype Play Process Production Psyche structure Research Resolution Role Site Societies Source Spinal Cord Surface Technology Testing Therapeutic base cell type chemokine design extracellular foot insight neuroinflammation neuropathology neurovascular unit novel oligodendrocyte-myelin glycoprotein protein distribution research study

项目摘要

The chemokine CCL2 is considered a significant factor in multiple sclerosis (MS), and plays a primary pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Though CCL2 nonredundantly functions in EAE to promote accumulation of destructive leukocytes in the central nervous system (CNS), as well as possibly other manifestations of neuroinflammation, neither the pathogenic source(s) of this chemokine, nor its site(s) and mechanism(s) of action, are known. And while astrocytes and endothelial cells are recognized as major sources of CCL2 during EAE, no descriptions have yet reconciled whether and how production of CCL2 by either of these cells leads to leukocyte extravasation and invasion of the CNS parenchyma. This deficiency leaves a significant void in understanding MS/EAE pathogenesis, and seriously impacts novel treatments for MS, as the potential of anti-CCL2 therapy is critically dependent on effectively disrupting the specific chemokine pool(s) responsible for disease activity. Accordingly, experiments are designed to begin testing the following broad hypothesis: Cell-specific release of CCL2 regulates discrete aspects of neuroinflammation during EAE. Aim 1 will focus on performing the first high-resolution analysis of CCL2 protein distribution in the CNS throughout the course of EAE, which will provide insight into those pathways of communication between centrally derived CCL2 and blood-borne leukocytes critical for guiding extravastion. Aim 2 will then employ two novel, cell-conditional CCL2 knockout lines - suffering targeted CCL2 elimination in astrocytes or endothelial cells - to determine the respective contributions of each of these cell types to clinical disease. These experiments will provide a foundation for future studies to further resolve the mechanisms by which CCL2 promotes leukocyte extravastion into the CNS, and highlight therapeutic avenues to most efficiently disrupt CCL2 action during CNS inflammatory disease.

趋化因子 CCL2 被认为是多发性硬化症 (MS) 的重要因素，并发挥着重要作用实验性自身免疫性脑脊髓炎（EAE）动物模型中的主要致病作用对于女士。尽管 CCL2 在 EAE 中非冗余地发挥作用，促进破坏性物质的积累中枢神经系统 (CNS) 中的白细胞，以及可能的其他表现神经炎症，既不是该趋化因子的致病源，也不是其位点和作用机制是已知的。虽然星形胶质细胞和内皮细胞被识别作为 EAE 期间 CCL2 的主要来源，目前尚无描述是否以及如何协调这些细胞产生 CCL2 会导致白细胞外渗和侵袭中枢神经系统实质。这一缺陷给 MS/EAE 的理解留下了重大空白发病机制，并严重影响 MS 的新疗法，因为抗 CCL2 的潜力治疗主要取决于有效破坏特定趋化因子库负责疾病活动。因此，实验被设计来开始测试遵循广泛的假设：CCL2 的细胞特异性释放调节各个方面 EAE 期间的神经炎症。目标 1 将侧重于执行首次高分辨率分析在整个 EAE 过程中 CCL2 蛋白在 CNS 中的分布，这将提供见解进入中枢衍生的 CCL2 和血源性细胞之间的通讯途径白细胞对于引导外渗至关重要。目标 2 将采用两种新颖的细胞条件 CCL2 敲除系 - 在星形胶质细胞或内皮细胞中遭受靶向 CCL2 消除 - 确定每种细胞类型对临床疾病的各自贡献。这些实验将为未来的研究提供基础，以进一步解决该机制其中 CCL2 促进白细胞外渗至中枢神经系统，并突出治疗途径在 CNS 炎症性疾病期间最有效地破坏 CCL2 的作用。