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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

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）是一种中枢神经系统的炎症性疾病，全世界有100万人患有不明病因。患有MS的人可以经历复发缓解或进行性形式的疾病，后者与皮质萎缩和认知能力下降。虽然MS 传统上被认为是一种白色物质的疾病，最近的证据表明，皮质病变在早期MS中很常见，并且随着年龄的增长，在MS的晚期阶段的丰度表明它们可能是重要的治疗靶点。B细胞是直接参与MS病理学，最近的证据表明病理学中存在IgG介导的脱髓鞘以及抗B细胞疗法治疗MS的有效性。然而，对皮质损伤的损伤和修复还不完全了解。对MS的理解已经取得了进展，由于缺乏能概括疾病特征的动物模型，皮质脱髓鞘的动态变化。为了克服这些限制，我们开发了 MS抗体依赖性脱髓鞘的新型小鼠模型和可视化髓鞘的方法，少突胶质细胞和它们的前体在活的小鼠脑中。在这里，我们建议利用这些创新的方法来辨别脱髓鞘的动力学和修复皮质病变中的髓鞘。的本研究的目的是：1）建立和评价一种新的抗体介导的皮质MS模型脱髓鞘和2）阐明皮质病变中髓鞘再生的潜在机制。这项建议通过开发新的方法来了解皮层病变的潜在机制，其表征MS并提供体内小鼠模型平台，其将允许评价新的 MS的治疗候选物。