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Identification of novel small molecules for CNS myelin repair

鉴定用于中枢神经系统髓磷脂修复的新型小分子

基本信息

批准号：
8485700
负责人：
JIANRONG LI
金额：
$ 18.47万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8485700
关键词：
Acute Adult Animal Model Animals Axon Biological Assay Cell Differentiation process Cell Maturation Cells Chemicals Clinic Demyelinating Diseases Demyelinations Development Disease Embryo Event Exploratory/Developmental Grant Failure Fluorescence Functional disorder Gliosis Goals Imagery Inflammatory Injury Laboratories Lead Lesion Libraries Life Medical center Membrane Mental disorders Modeling Multiple Sclerosis Myelin Myelin Sheath Natural regeneration Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Oligodendroglia Peripheral Nervous System Periventricular Leukomalacia Pharmaceutical Preparations Premature Infant Process Proteins Recovery of Function Relapsing-Remitting Multiple Sclerosis Schizophrenia Spinal cord injury System Technology Testing Time Toxin Transgenic Mice Transgenic Organisms base central nervous system demyelinating disorder in vivo innovation myelination nervous system disorder neurodevelopment novel novel therapeutic intervention oligodendrocyte precursor postnatal precursor cell progenitor promoter relating to nervous system remyelination repaired response screening selective expression small molecule small molecule libraries tool

项目摘要

DESCRIPTION (provided by applicant): Myelination of axons is essential for the normal function of the vertebrate central nervous system (CNS), and is a multi-step process that requires oligodendrocyte precursor cells (OPCs) to recognize target axons and differentiate into myelinating cells. Although myelination occurs primarily in early postnatal life, it can be re- initiated in adult CNS in response to demyelinating injury. This remyelination process is, however, limited in demyelinating diseases such as multiple sclerosis, in part due to the failure of OPCs to differentiate into mature oligodendrocytes. As remyelination promotes axonal survival and functional recovery, how to coax OPCs to differentiate into myelinating cells represents a critical step in achieving myelin repair and functional recovery. Currently, there is no clinic therapy aimed at promoting myelin repair. Thus, the goal of this proposal is to identify small molecules that promote OPCs to differentiate into myelinating cells. We will employ a novel CNS myelinating culture system recently established in our laboratory to screen a chemical library consisting of 200,000-drug-like compounds. To achieve high throughput and direct visualization of oligodendrocyte maturation, we will use cultures derived from our newly generated transgenic mice where membrane-anchored enhanced green fluorescence protein is selectively expressed in myelin sheaths and mature oligodendrocytes. Lead compounds identified by chemical screening will then be tested in culture for their efficacy in promoting OPCs into myelinating cells and in an animal model of demyelination. This proposed study has the potential to lead to the development of novel therapeutic interventions aimed at promoting myelin regeneration and functional recovery.

描述（由申请人提供）：轴突的髓鞘形成对于脊椎动物中枢神经系统（CNS）的正常功能至关重要，是一个多步骤的过程，需要少突胶质前体细胞（OPCs）识别目标轴突并分化成髓鞘细胞。虽然髓鞘形成主要发生在出生后早期，但它可以在成人中枢神经系统中重新启动，以应对脱髓鞘损伤。然而，这种髓鞘再生过程在脱髓鞘疾病（如多发性硬化症）中受到限制，部分原因是OPCs不能分化为成熟的少突胶质细胞。髓鞘再生促进轴突存活和功能恢复，如何诱导OPCs分化成髓鞘细胞是实现髓鞘修复和功能恢复的关键一步。目前，临床上尚无旨在促进髓磷脂修复的治疗方法。因此，本研究的目标是鉴定促进OPCs分化为髓鞘细胞的小分子。我们将使用我们实验室最近建立的一种新型中枢神经系统髓鞘培养系统来筛选由20万种药物样化合物组成的化学文库。为了实现少突胶质细胞成熟的高通量和直接可视化，我们将使用来自我们新生成的转基因小鼠的培养物，其中膜锚定的增强绿色荧光蛋白在髓鞘和成熟的少突胶质细胞中选择性表达。通过化学筛选鉴定出的先导化合物将在培养物中测试其促进OPCs进入髓鞘细胞的功效，并在脱髓鞘动物模型中进行测试。这项研究有可能导致新的治疗干预措施的发展，旨在促进髓磷脂再生和功能恢复。