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

表征氧甾醇（20-羟基胆固醇）作为多发性硬化症髓鞘再生介质的作用

• 批准号: 10311395
• 负责人: Eric J Benner
• 金额: $ 44.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311395
• 关键词: Acute; Adult; Affect; Animal Model; Autoimmune Diseases; Axon; Behavior; Cell Differentiation process; Cell Nucleus; Cells; Cerebral Palsy; Clinical; Complex; Corpus Callosum; Cuprizone; Data; Demyelinations; Development; Disease; Disease Management; Disease remission; Foundations; Gene Expression; Gene Expression Profiling; Goals; Health; Hydroxycholesterols; Immune; Immune system; Individual; Inflammatory Response; Knowledge; Maps; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Analysis; Multiple Sclerosis; Mus; Natural regeneration; Nerve Degeneration; Neuraxis; Neurologic Symptoms; Neurological outcome; Neurons; Oligodendroglia; Outcome; Pathogenesis; Pathogenicity; Pathologic Processes; Pathway interactions; Pharmacotherapy; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Play; Population; Process; Regulation; Research; Resolution; Rewards; Risk; Role; Running; Severity of illness; Signal Transduction; Site; Structure; Symptoms; Testing; Therapeutic; TimeLine; Transgenic Mice; Transmission Electron Microscopy; Withdrawal; autoreactive T cell; autoreactivity; base; behavior test; behavioral response; curative treatments; design; dietary; experience; field study; improved; in situ sequencing; injury and repair; motor control; multiple sclerosis patient; nervous system disorder; neurodegenerative phenotype; novel; novel therapeutics; oligodendrocyte precursor; oligodendrocyte progenitor; precursor cell; remyelination; stem cells; therapeutic development; transcriptomics; white matter; white matter injury; young adult

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.

多发性硬化症（MS）是成年的最常见神经系统疾病，影响大约1 美国的百万个人和全球250万人。 MS是免疫介导的自身免疫性疾病 引发中枢神经系统（CNS）的脱髓鞘和神经元损伤的细胞，导致 神经系统症状使人衰弱。虽然已证明改善疾病的疗法是有效的，但它们仅 延长缓解，他们不会改变疾病病程，大多数具有MS的人可能会 在疾病过程中，临床症状的经历恶化。有很大的差距 关于MS的治疗疗法的知识，该疗法促使少突胶质细胞前体细胞分化 进入成熟的少突胶质细胞（ODS），这是成年中枢神经系统内的主要再生细胞。提出令人兴奋 成年小鼠的白质损伤模型中的初步数据确定了20-羟基胆脂酯（20HC） 能够触发中枢神经系统的再髓式，并且能够将新的OD与 在疾病期间发生的有限自发再生之外，中枢神经系统中的OPC静止库 课程。该重新提议的提议建立在此动物模型中的这种令人回味的初步数据基于 脱髓鞘并提出了前沿分子方法的应用 20HC效应的机制。该提案的长期目标是确定20HC的功效 逆转MS的渐进过程的新型药物。