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

项目摘要 多发性硬化症(MS)是一种中枢神经系统炎症性疾病，影响超过2.5 全世界有一百万人的病因不明。患有多发性硬化症的人可能会经历复发-缓解或 进行性疾病，后者与皮质萎缩和认知衰退有关。而微软则是 传统上被认为是一种白质疾病，最近的证据表明有大量的髓鞘 多发性硬化症患者的灰质丢失皮质损害在多发性硬化症早期很常见，而且还在增加 多发性硬化症晚期的丰富提示它们可能是一个重要的治疗靶点。B细胞是 直接与多发性硬化症病理有关，最近的证据表明免疫球蛋白介导的脱髓鞘在病理中有牵连 抗B细胞疗法治疗多发性硬化症的有效性然而，调节髓鞘的机制 皮质损伤的损伤和修复尚不完全清楚。对多发性硬化症的认识已经取得了进展 受制于缺乏概括疾病特征的动物模型以及无法检测到 活体患者皮质脱髓鞘的动力学。为了克服这些限制，我们开发了 一种新的多发性硬化症抗体依赖性脱髓鞘小鼠模型和显示髓鞘的方法， 少突胶质细胞及其前体在活着的小鼠脑中。在这里，我们建议利用这些 识别皮质损伤中脱髓鞘和修复髓鞘动力学的创新方法。这个 该方案的目的是：1)开发和评估抗体介导的多发性硬化症皮质新模型 脱髓鞘和2)阐明皮质损伤中重新髓鞘形成的机制。这项建议 通过开发新的方法来了解皮质损伤的机制，取得了新的突破 这是多发性硬化症的特征，并提供了体内小鼠模型平台，将允许评估新的 治疗多发性硬化症的候选药物

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.