Drug-mediated enhancement of myelination

 描述(由申请人提供)：多发性硬化症(MS)是一种复杂的、令人衰弱的神经疾病，与显著的发病率和死亡率有关。疾病的病因是未知的环境和遗传因素的结果，而疾病的病理表现为中枢神经系统(CNS)的炎症性损伤，导致身体丧失能力。这种损伤是自身免疫介导的少突胶质细胞破坏导致脱髓鞘的结果。根据疾病的表现，长期脱髓鞘导致轴突损伤发生在局灶性病变部位和/或广泛分布于整个中枢神经系统。MS使用针对免疫系统的疾病改良剂进行治疗，以试图减少复发的频率并延缓疾病的进展。这些药物在改善患者预后方面的成功有限，而且缺乏促进立即重新髓鞘形成的未得到满足的需求。识别诱导常驻少突胶质前体细胞(OPC)介导的重新髓鞘形成的药物将为患者提供阻止疾病进展和改善功能的重要机制。利用创新的基于多能干细胞的高通量筛选平台，我们发现了一类FDA批准的药物，可以增强MS小鼠模型的再髓鞘形成。在这项资助中，我们将使用体内和体外模型来研究这类药物对小鼠和人类OPC的细胞和分子效应。这些研究将为这种药物或修饰的衍生物潜在地转化为临床试验提供基础，作为一种重新髓鞘疗法。

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex, debilitating neural disorder associated with significant morbidity and mortality. Disease etiology is a result o unknown environmental and genetic factors, while disease pathology presents as inflammatory injury to the central nervous system (CNS) causing physical incapacity. This damage is a result of autoimmune-mediated destruction of oligodendrocytes causing demyelination. Prolonged demyelination leads to axonal damage occurring either in focal lesion sites and/or widespread throughout the CNS, depending on presentation of the disease. MS is treated with disease-modifying agents that target the immune system in an attempt to reduce the frequency of relapses and delay disease progression. These drugs have had limited success in improving patient outcomes and lack the unmet need to promote immediate remyelination. Identifying drugs that induce resident oligodendrocyte progenitor cell (OPC) mediated remyelination would provide patients a vital mechanism to halt disease progression and improve function. Using an innovative pluripotent stem cell-based high throughput screening platform we have discovered a class of FDA approved drugs that enhance remyelination in mouse models of MS. In this grant we will use in vivo and in vitro models to study the cellular and molecular effects of this class o drugs on mouse and human OPCs. These studies will provide the basis for potential translation of this drug, or modified derivatives, to clinical testing as a remyelinating therapeutic.