Characterizing the oxysterol, 20-hydroxycholesterol, as a mediator of remyelination in multiple sclerosis

多发性硬化症(MS)是青壮年最常见的神经系统疾病，估计有1 美国有100万人，全球有250万人。MS是一种由免疫介导的自身免疫性疾病 触发中枢神经系统(CNS)脱髓鞘和神经元损伤的细胞，导致 衰弱的神经症状。虽然疾病修正疗法已被证明是有效的，但它们只有 延长缓解期，它们不会改变病程，大多数多发性硬化症患者很可能 在他们的疾病过程中经历临床症状恶化。在这方面有很大差距 关于促进少突胶质前体细胞分化的多发性硬化症治疗方法的知识 分化成成熟的少突胶质细胞(OD)，这是成人中枢神经系统内主要的再髓鞘细胞。展示的是令人兴奋的 建立20-羟基雌酚(20HC)的成年小鼠白质损伤模型的初步数据 能够触发中枢神经系统的再髓鞘形成，并能够区分新的ODs和 中枢神经系统中静止的OPC池，超出疾病期间发生的有限的自发再生 当然了。这份重新提交的提案建立在一个动物模型的初步数据基础上 脱髓鞘，并提出应用前沿分子方法来理解 20HC效应的机制。这项提案的长期目标是确定20HC作为一种完全 逆转MS进展性进程的新药

Multiple sclerosis (MS) is the most common neurological disease of young adulthood, affecting an estimated 1 million individuals in the U.S. and 2.5 million worldwide. MS is an autoimmune disease mediated by immune cells that trigger demyelination and neuronal damage of the central nervous system (CNS), resulting in debilitating neurological symptoms. While disease-modifying therapies have proven to be efficacious, they only prolong remission, they do not change disease course, and the majority of individuals with MS will likely experience worsening of clinical symptoms during the course of their disease. There is a significant gap in knowledge with respect to curative therapies for MS that prompt oligodendrocyte precursor cells to differentiate into mature oligodendrocytes (ODs), the main remyelinating cells within the adult CNS. Presented are exciting preliminary data in a white matter injury model of adult mice that establishes that 20-hydroxycholestrol (20HC) is capable of triggering remyelination in the CNS, and that it is capable of differentiating new ODs from the quiescent pool of OPCs in the CNS beyond the limited spontaneous regeneration that occurs during disease course. This resubmitted proposal builds upon this evocative preliminary data in an animal model of demyelination and proposes the application of leading edge molecular approaches to understanding the mechanisms of 20HC effect. The long-term goal of this proposal is to identify the efficacy of 20HC as a completely novel drug for reversing the progressive course of MS.