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

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

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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）：轴突的髓鞘化对于脊椎动物中枢神经系统（CNS）的正常功能至关重要，并且是一个多步骤过程，需要少突胶质细胞前体细胞（OPC）识别靶轴突并区分髓线细胞。尽管髓鞘形成主要发生在产后早期，但可以在成年中枢神经系统中启动，以响应脱髓鞘损伤。然而，这种透明化过程受到脱髓鞘疾病（例如多发性硬化症）的限制，部分原因是OPC未能分化为成熟的少突胶质细胞。随着透明度促进轴突存活和功能恢复，如何哄骗OPC分化为髓线细胞代表了实现髓磷脂修复和功能恢复的关键步骤。目前，尚无旨在促进髓磷脂修复的临床疗法。因此，该提案的目的是确定促进OPC的小分子，以分化为髓生成细胞。我们将采用最近在我们的实验室中建立的新型CNS髓鞘化培养系统，以筛选由200,000种类似药物的化合物组成的化学库。为了实现少突胶质细胞成熟的高吞吐量和直接可视化，我们将使用源自新生成的转基因小鼠的培养物，其中在髓磷脂鞘和成熟的少突胶质细胞中选择性地表达了膜的增强的增强的增强的绿色荧光蛋白。然后，通过化学筛选确定的铅化合物将在培养物中测试其在将OPC促进骨髓细胞和脱髓鞘模型中的功效。这项拟议的研究有可能导致旨在促进髓磷脂再生和功能恢复的新型治疗干预措施的发展。