CD200 signaling mediates the interactions of neurons and endothelia with circulating leukocytes in stroke

CD200 信号传导介导中风中神经元和内皮细胞与循环白细胞的相互作用

• 批准号: 10737356
• 负责人: Fudong Liu
• 金额: $ 56.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737356
• 关键词: Adult; Affect; Aging; Area; Astrocytes; Binding; Blood; Bone Marrow; Brain; Brain Ischemia; CD 200; Calcium; Cells; Central Nervous System Diseases; Chimera organism; Coupling; Data; Disease; Elderly; Endothelium; Failure; Female; Flow Cytometry; Glial Fibrillary Acidic Protein; Glycoproteins; Green Fluorescent Proteins; Immune; Immune response; Immunologic Receptors; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interruption; Ischemic Brain Injury; Ischemic Stroke; Knock-out; Knockout Mice; Leucocytic infiltrate; Leukocytes; Lifting; Ligands; LoxP-flanked allele; Lymphocyte; Macrophage; Mediating; Membrane; Microglia; Middle Cerebral Artery Occlusion; Mouse Protein; Mus; Myeloid Cells; Neurons; Organ; Outcome; Oxidative Stress; Pathway interactions; Peripheral; Play; Process; Public Health; Research; Rest; Role; Signal Transduction; Stroke; Testing; Time; Transfection; Transgenic Mice; Translating; Transplantation; Up-Regulation; Virus; aged; behavioral outcome; brain cell; brain endothelial cell; cadherin 5; comparison intervention; conditional knockout; cytokine; enolase; excitotoxicity; immune activation; improved outcome; in vivo; knock-down; male; migration; mouse model; neuroinflammation; neutrophil; overexpression; post stroke; pre-clinical; prevent; promoter; receptor; stroke outcome; stroke patient; stroke therapy; therapeutic target; therapeutically effective; tissue injury

PROJECT SUMMARY Immune responses are a fundamental pathophysiological process that significantly contribute to ischemic brain injury. Holding the immune response in check can alleviate the delayed injury seen in stroke and has considerable translational value. CD200 binds to its receptor, CD200R, that is expressed on immune cells. This forms an endogenous inhibitory signal and reduces the activation of immune cells. The traditional notion that the neuronal-microglial CD200-CD200R interaction is the key to suppressing deleterious immune activation has been increasingly questioned, as accumulating data has shown that the CD200R is expressed on peripheral immune cells but not on adult microglia. In this proposal we hypothesize that the CD200-CD200R signaling axis inhibits mobilization of peripheral immune cells after stroke, and that interruption of CD200-CD200R interaction will exacerbate both central (brain) and peripheral immune responses. We will specifically examine the CD200-CD200R axis from both ends, by manipulating either CD200 or the CD200R to determine the effects on peripheral immune cell activation and stroke injury. In Aim 1, we will use a bone marrow chimera mouse model generated from global CD200R knockout and GFP+ mice, to determine the contribution of peripheral vs. central (brain) CD200- CD200R signaling to stroke outcomes. Aim 2 will investigate the effect of endothelial CD200 signaling on peripheral leukocyte migration in the ischemic brain. Brain endothelial CD200 knockdown (by AAV-BR1-Cre virus) and lenti-CD200 virus (conjugated with endothelial specific promotor Cadherin 5) transfected mice will be used to examine the effects of down-/up-regulation of endothelial CD200 respectively on immune responses to stroke. Aim 3 will evaluate the role of neuronal CD200 signaling in post-stroke inflammation and stroke outcomes. Neuronal CD200 CKO mice (CD200fl/fl:Eno2-Cre) and lenti-CD200 virus on neuronal promotor Enolase 2 (Eno2) will be used. As CD200-CD200R signaling functions in various neuroinflammatory diseases, the proposed project will open up a new area of CD200-CD200R research not only in stroke, but also in other central nervous system disorders.

项目摘要 免疫反应是一个基本的病理生理过程，显著促进缺血性心脏病的发生。 脑损伤控制免疫反应可以减轻中风中出现的迟发性损伤， 具有相当大的翻译价值。CD 200与其受体CD 200 R结合，CD 200 R在免疫细胞上表达， 细胞这形成内源性抑制信号并减少免疫细胞的活化。的 传统观点认为，神经元-小胶质细胞CD 200-CD 200 R相互作用是抑制CD 200表达的关键。 有害的免疫激活越来越受到质疑，因为积累的数据表明， CD 200 R在外周免疫细胞上表达，但在成人小胶质细胞上不表达。在本提案中，我们 假设CD 200-CD 200 R信号传导轴抑制外周免疫细胞的动员， 中风，且CD 200-CD 200 R相互作用中断将加重中枢（脑）和 外周免疫反应我们将从两端具体检查CD 200-CD 200 R轴， 操纵CD 200或CD 200 R以确定对外周免疫细胞活化的影响 和中风损伤。在目标1中，我们将使用从全球产生的骨髓嵌合体小鼠模型， CD 200 R敲除和GFP+小鼠，以确定外周与中枢（脑）CD 200- CD 200 R信号传导与卒中结局目的2将研究内皮细胞CD 200信号转导对内皮细胞凋亡的影响。 缺血性脑中的外周白细胞迁移。脑内皮CD 200敲低（通过AAV-BR 1-Cre 病毒）和慢-CD 200病毒（与内皮特异性启动子钙粘蛋白5缀合）转染的小鼠将 分别检测内皮细胞CD 200下调/上调对免疫功能的影响， 对中风的反应目的3将评估神经元CD 200信号在卒中后炎症中的作用 和中风的结果。神经元CD 200 CKO小鼠（CD 200 fl/fl：Eno 2-Cre）和慢病毒-CD 200病毒对神经元 将使用启动子烯醇化酶2（Eno 2）。由于CD 200-CD 200 R信号转导功能在各种 神经炎性疾病，拟议的项目将开辟一个新的领域，CD 200-CD 200 R的研究不 不仅在中风中，而且在其他中枢神经系统疾病中。