The role of microglia in neuromyelitis optica

小胶质细胞在视神经脊髓炎中的作用

基本信息

批准号：
9884293
负责人：
VANDA A LENNON
金额：
$ 46.15万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9884293
关键词：
Ablation Address Affect Agonist Astrocytes Autoantibodies Autoimmune Diseases Autoimmunity Automobile Driving Behavioral Binding Blindness Cells Cessation of life Communication Complement Complement 3a Coupled Data Demyelinations Designer Drugs Development Disease Event Evolution Functional disorder Future GTP-Binding Proteins Genetic Image Immune Immunoglobulin G Immunosuppression Impairment Inflammation Inflammatory Infusion procedures Knockout Mice Lesion Mediating Membrane Microglia Minocycline Modeling Molecular Morbidity - disease rate Motor Multiple Sclerosis Mus Nature Nerve Degeneration Neuraxis Neuroimmune Neuromyelitis Optica Neuronal Dysfunction Neuronal Injury Optic Nerve Outcome Oxidative Stress Paralysed Pathogenesis Pathogenicity Pathologic Patients Pattern Pharmacology Prevention Process Production Proteins Protons Relapse Research Role Secondary to Spinal Cord Spinal Cord Lesions Sum Technology Testing Therapeutic Time aquaporin 4 conventional therapy designer receptors exclusively activated by designer drugs diphtheria toxin receptor experience experimental study genetic approach improved inhibitor/antagonist monocyte motor disorder motor impairment mouse model nervous system disorder neuroinflammation novel prevent receptor response selective expression therapeutic target tool two-photon voltage water channel

Ablation Address Affect Agonist Astrocytes Autoantibodies Autoimmune Diseases Autoimmunity Automobile Driving Behavioral Binding Blindness Cells Cessation of life Communication Complement Complement 3a Coupled Data Demyelinations Designer Drugs Development Disease Event Evolution Functional disorder Future GTP-Binding Proteins Genetic Image Immune Immunoglobulin G Immunosuppression Impairment Inflammation Inflammatory Infusion procedures Knockout Mice Lesion Mediating Membrane Microglia Minocycline Modeling Molecular Morbidity - disease rate Motor Multiple Sclerosis Mus Nature Nerve Degeneration Neuraxis Neuroimmune Neuromyelitis Optica Neuronal Dysfunction Neuronal Injury Optic Nerve Outcome Oxidative Stress Paralysed Pathogenesis Pathogenicity Pathologic Patients Pattern Pharmacology Prevention Process Production Proteins Protons Relapse Research Role Secondary to Spinal Cord Spinal Cord Lesions Sum Technology Testing Therapeutic Time aquaporin 4 conventional therapy designer receptors exclusively activated by designer drugs diphtheria toxin receptor experience experimental study genetic approach improved inhibitor/antagonist monocyte motor disorder motor impairment mouse model nervous system disorder neuroinflammation novel prevent receptor response selective expression therapeutic target tool two-photon voltage water channel

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项目摘要

Neuromyelitis optica (NMO) is a severe, relapsing IgG-mediated autoimmune disease targeting the central nervous system (CNS), inducing inflammation and preferential demyelination of optic nerve and spinal cord. Most patients experience severe impairments. IgG autoantibodies specific for the astrocytic aquaporin-4 (AQP4) water channel are the primary cause of the disease pathophysiology. However, little is known about the mechanisms driving NMO lesion progression following the binding of IgG to the astrocyte membrane on entering the CNS. Our proposed project will investigate the potential contribution of microglia, the resident immune cell of the CNS, to the evolving NMO lesion. We have developed an informative mouse model of NMO. NMO-IgG is infused intrathecally. Our preliminary results show significant motor dysfunction, astrocyte activation, and a unique pattern of early microglial convergence on astrocytes. Prevention of microglial activity suppressed development of motor dysfunction. In sum, these data clearly indicate astrocyte-microglia communication as an early event after NMO-IgG enters the CNS. Aim 1, will investigate the mechanisms underlying astrocyte-microglia crosstalk; Aim 2, will assess the contribution of microglia to NMO pathogenesis, and Aim 3 will utilize novel genetic tools to manipulate microglial activity as a potential therapeutic approach to NMO management. The research we propose represents the first attempt to investigate the specific contribution of microglia to NMO pathogenesis. The results should clarify the importance of astrocyte-microglia crosstalk and its underlying mechanisms in NMO. The study will not only improve understanding of neuroimmune interaction in NMO but will potentially establish that microglia are a pertinent target for NMO therapy.

神经霉炎Optica（NMO）是一种严重的，具有IgG介导的自身免疫性疾病，旨在中枢神经系统（CNS），诱导炎症和视神经的优先脱髓鞘脊髓。大多数患者遭受严重损害。 IgG自身抗体针对星形胶质细胞的特异性水通道4（AQP4）水通道是疾病病理生理学的主要原因。然而，关于在IgG结合后驱动NMO病变进展的机制知之甚少星形胶质细胞膜进入中枢神经系统。我们提议的项目将调查潜力中枢神经系统的驻留免疫细胞小胶质细胞对不断发展的NMO病变的贡献。我们有开发了NMO的鼠标模型。 NMO-IGG持发式地注入。我们的初步结果显示明显的运动功能障碍，星形胶质细胞激活和早期小胶质细胞的独特模式星形胶质细胞的收敛性。预防小胶质细胞活性抑制了电动机的发展功能障碍。总而言之，这些数据清楚地表明星形胶质细胞 - 麦克罗利亚通信作为早期事件 NMO-IGG进入CNS之后。 AIM 1将调查星形胶质细胞 - 形crosstalk的基础机制； AIM 2，将评估小胶质细胞对NMO发病机理的贡献，AIM 3将利用新型的遗传工具来操纵小胶质活性是NMO管理的潜在治疗方法。我们提出的研究是研究小胶质细胞的特定贡献的首次尝试 NMO发病机理。结果应阐明星形胶质细胞 - 形crosstalk及其的重要性 NMO中的基本机制。这项研究不仅会改善对神经免疫的理解 NMO中的相互作用，但有可能确定小胶质细胞是NMO治疗的相关靶标。