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）是最常见的神经系统疾病的年轻成年人，影响估计1 在美国有250万人，在全世界有250万人。MS是一种免疫介导的自身免疫性疾病， 细胞，其触发中枢神经系统（CNS）的脱髓鞘和神经元损伤，导致 使人衰弱的神经症状虽然疾病修饰疗法已被证明是有效的，但它们仅 延长缓解，他们不改变病程，大多数MS患者可能会 在他们的疾病过程中经历临床症状恶化。有一个重大的差距， 关于促进少突胶质细胞前体细胞分化MS治愈性疗法的知识 成熟的少突胶质细胞（OD），成年CNS内的主要髓鞘再生细胞。呈现令人兴奋 成年小鼠白色损伤模型的初步数据，该模型确定20-羟基胆固醇（20 HC） 能够触发CNS中的髓鞘再生，并且能够将新的OD与 CNS中OPCs的静止池超出疾病期间发生的有限自发再生 当然了这个重新提交的提案是建立在动物模型中令人回味的初步数据基础上的。 脱髓鞘，并提出了应用前沿分子方法来了解脱髓鞘的作用。 20 HC效应的机制。该提案的长期目标是确定20 HC作为完全缓解的有效性。 用于逆转MS进展过程的新药。