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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

基本信息

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
项目类别：
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

项目摘要

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）是年轻人中最常见的神经系统疾病，据估计影响全球约1亿人