Oligodendrocytes and their Precursors in a Novel Model of Antibody-Mediated Cortical Demyelination

抗体介导的皮质脱髓鞘新模型中的少突胶质细胞及其前体

基本信息

批准号：
9507374
负责人：
Ethan Garrett Hughes
金额：
$ 23.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9507374
关键词：
Affect Animal Model Antibodies Antibody Formation B cell therapy B-Lymphocytes Biology Brain Cell Lineage Central Nervous System Diseases Clinical Demyelinations Disease Effectiveness Etiology Evaluation Failure Future Goals Image Immune Immunoglobulin G Impaired cognition Individual Inflammatory Injections Injury Kinetics Left Lesion Mediating Meningeal Methods Modeling Multiple Sclerosis Mus Myelin Oligodendroglia Outcome Pathogenesis Pathology Patients Plasmablast Recombinant Antibody Recombinants Recovery Relapse Research Surface Testing Thalamic structure Time Tissues Validation White Matter Disease cell motility cerebral atrophy experience gray matter in vivo injury and repair innovation insight mouse model multiple sclerosis patient multiple sclerosis treatment new therapeutic target novel novel strategies novel therapeutics oligodendrocyte lineage oligodendrocyte precursor recruit remyelination repaired response therapeutic candidate therapeutic target

Affect Animal Model Antibodies Antibody Formation B cell therapy B-Lymphocytes Biology Brain Cell Lineage Central Nervous System Diseases Clinical Demyelinations Disease Effectiveness Etiology Evaluation Failure Future Goals Image Immune Immunoglobulin G Impaired cognition Individual Inflammatory Injections Injury Kinetics Left Lesion Mediating Meningeal Methods Modeling Multiple Sclerosis Mus Myelin Oligodendroglia Outcome Pathogenesis Pathology Patients Plasmablast Recombinant Antibody Recombinants Recovery Relapse Research Surface Testing Thalamic structure Time Tissues Validation White Matter Disease cell motility cerebral atrophy experience gray matter in vivo injury and repair innovation insight mouse model multiple sclerosis patient multiple sclerosis treatment new therapeutic target novel novel strategies novel therapeutics oligodendrocyte lineage oligodendrocyte precursor recruit remyelination repaired response therapeutic candidate therapeutic target

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项目摘要

Project Summary Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that affects more than 2.5 million people worldwide with an unknown etiology. People with MS can experience relapsing-remitting or progressive forms of disease, with the latter associated with cortical atrophy and cognitive decline. While MS is classically regarded as a disease of the white matter, recent evidence suggests that there is significant myelin loss in the gray matter of patients with MS. Cortical lesions are common in early MS and their increasing abundance during late stages of MS suggests that they may be an important therapeutic target. B cells are directly implicated in MS pathology, with recent evidence implicating IgG-mediated demyelination in pathology and the effectiveness of anti-B cell therapies in treatment of MS. However, mechanisms regulating myelin injury and repair in cortical lesions are incompletely understood. Progress in the understanding of MS has been constrained by the paucity of animal models that recapitulate hallmarks of the disease and inability to detect the dynamics of cortical demyelination in living patients. To overcome these limitations, we have developed both a novel mouse model of MS antibody-dependent demyelination and approaches to visualize myelin, oligodendrocytes, and their precursors in the living mouse brain. Here we propose to capitalize on these innovative approaches to discern the dynamics of demyelination and repair myelin in cortical lesions. The objectives of this proposal are: 1) Develop and evaluate a new model of antibody-mediated MS cortical demyelination and 2) Elucidate the mechanisms underlying remyelination in cortical lesions. This proposal breaks new ground by developing novel approaches to understand the mechanisms underlying cortical lesions that characterize MS and provide an in vivo mouse model platform that will allow for the evaluation of new therapeutic candidates for MS.

项目摘要多发性硬化症（MS）是中枢神经系统的炎症性疾病，影响超过2.5 全球有一个未知的病因。患有MS的人可以经历复发的复发或疾病的进行性形式，后者与皮质萎缩和认知能力下降有关。而MS是在经典上被认为是白质的疾病，最近的证据表明有明显的髓磷脂 MS患者的灰质损失。皮质病变在早期MS及其增加 MS后期的丰度表明它们可能是重要的治疗靶点。 B细胞是直接与MS病理有关，最近的证据涉及IgG介导的病理脱髓鞘以及抗B细胞疗法在MS治疗中的有效性。但是，调节髓鞘的机制皮质病变的损伤和修复尚不完全了解。理解MS的进展已经受动物模型的匮乏的限制，这些模型概括了该疾病的标志并无法检测活着的患者皮质脱髓鞘的动力学。为了克服这些限制，我们已经发展了 MS抗体依赖性脱髓鞘的新型小鼠模型和可视化髓磷脂的方法，活着的小鼠大脑中的少突胶质细胞及其前体。在这里，我们建议利用这些创新的方法来辨别皮质病变中脱髓鞘和修复髓磷脂的动态。这该建议的目标是：1）开发和评估抗体介导的MS皮质的新模型脱髓鞘和2）阐明了皮质病变中延期性的机制。这个建议通过开发新的方法来理解皮质病变的机制，从而打破新的基础该特征是MS并提供一个体内鼠标模型平台，该平台将允许评估新的 MS的治疗候选人。