Oligodendrocyte ontogeny and differentiation

描述(申请人提供)：中枢神经系统中的少突胶质细胞的主要功能是产生包裹轴突的髓鞘，并允许神经冲动的快速跳跃传导。我们的长期目标是阐明髓鞘形成的过程及其调控。由于髓鞘碱性蛋白(MBP)是髓鞘的主要和必需成分，因此我们重点分析控制其表达的机制。MBP是在髓鞘中的组装部位合成的。这是通过将其mRNA从细胞核运输到细胞体，并沿着细胞突起进一步向下进入髓鞘来实现的，在那里它被锚定和翻译。我们的目的是确定MBP mRNA中调节其翻译的元件、与这些元件结合的蛋白质及其作用方式，并表征MBP mRNA翻译的位置和启动它所必需的局部因素。在多发性硬化症等疾病中，在存在足够数量的早髓鞘少突胶质细胞的情况下，未能实现完全的再髓鞘形成，可能是由于少突胶质细胞部分缺乏接受性，部分神经元缺乏髓鞘信号，或者是由于其他类型的细胞(如星形胶质细胞)造成的髓鞘形成抑制条件。后一种情况似乎在多发性硬化症中起作用，并可能对MBP的表达产生直接负面影响。为了达到上述目的，我们将在培养的少突胶质细胞中进行体内翻译实验，以评估MBP mRNA中翻译调控元件的缺失及其特定的RNA结合蛋白的敲除的效果，并将在培养的少突胶质细胞和髓鞘组分中进行蛋白质-蛋白质相互作用的生物物理表征和翻译位点的免疫学分析。一些疾病，如多发性硬化症、病毒感染或辐射后症状，存在于人类中，这些疾病是由于大脑和脊髓中髓鞘的丢失造成的。患者走路或做日常家务都有困难。髓鞘是包裹轴突的一层膜，轴突是负责神经传导的神经元的一部分。我们的研究重点是找出髓鞘是如何产生的，以及如何修复它，可能是通过使用药理药物，使患者能够恢复参与正常生活活动的能力。

DESCRIPTION (provided by applicant): The major function of the oligodendrocyte in the CNS is to produce myelin that envelops axons and allows fast saltatory conduction of nerve impulses. Our long-term goal is to elucidate the process of myelination and its regulation. Since myelin basic protein (MBP) is a major and essential component of myelin we are focused on analyzing the mechanisms that control its expression. MBP is synthesized at its site of assembly in myelin. This is accomplished by transport of its mRNA from the nucleus to the cell body, and further down the cell processes and into myelin where it is anchored and translated. Our aims are to identify the elements in MBP mRNA that regulate its translation, the proteins that bind to these elements and their mode of action, and characterize the sites of MBP mRNA translation and the local factors that are necessary to initiate it. Failure to achieve full remyelination in the presence of adequate number of premyelinating oligodendrocytes in diseases such as multiple sclerosis may be due to the lack of receptivity on the part of the oligodendrocyte, lack of myelination signals on the part of the neuron, or to inhibiting conditions for myelination created by other cell types such as astrocytes. The latter conditions appear to be at play in multiple sclerosis and may have a direct negative effect on MBP expression. In order to accomplish the proposed aims the effects of deletion of translation regulatory elements in MBP mRNA, and knockdown of their specific RNA binding proteins will be assessed in an in vivo translation assay in cultured oligodendrocytes, and the characterization of protein-protein interactions by biophysical methods, and immnunological analysis of translation sites will be performed in cultured oligodendrocytes and in myelin fractions. Several diseases, such as multiple sclerosis, viral infections, or post-radiation symptom exist in humans that are due to the loss of myelin in the brain and the spinal cord. Patients have difficulty walking or doing daily chores. Myelin is a membrane that envelops the axon which is the part of the neuron responsible for nerve conduction. Our research focuses on finding out how myelin is made and how it can be repaired, possibly by the use of pharmacological drugs, so that patients could regain the ability to participate in normal life activities.