Oligodendrocyte ontogeny and differentiation

描述（由申请人提供）：中枢神经系统中少突胶质细胞的主要功能是产生髓磷脂，髓磷脂包裹轴突，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。髓鞘碱性蛋白（myelin basic protein， MBP）是髓磷脂的重要组成部分，因此我们重点分析其表达的调控机制。MBP在髓磷脂的组装部位合成。这是通过将mRNA从细胞核转运到细胞体，并进一步沿着细胞过程进入髓鞘，在髓鞘中锚定并翻译完成的。我们的目标是确定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模式，并表征MBP mRNA翻译的位点和启动它所必需的局部因子。在诸如多发性硬化症等疾病中，在存在足够数量的髓鞘前少突胶质细胞的情况下，不能实现完全的髓鞘再形成，可能是由于少突胶质细胞缺乏接受性，神经元缺乏髓鞘形成信号，或其他细胞类型（如星形胶质细胞）产生的髓鞘形成的抑制条件。后一种情况似乎在多发性硬化症中起作用，可能对MBP表达有直接的负面影响。为了实现所提出的目标，将在培养的少突胶质细胞中进行体内翻译试验，评估MBP mRNA中翻译调控元件的缺失及其特异性RNA结合蛋白的敲低的影响，并通过生物物理方法表征蛋白质-蛋白质相互作用，并在培养的少突胶质细胞和髓鞘中进行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，是由于大脑和脊髓髓磷脂的损失。患者行走或做日常家务有困难。髓鞘是包裹轴突的膜，轴突是神经元中负责神经传导的部分。我们的研究重点是找出髓磷脂是如何产生的，以及如何修复髓磷脂，可能是通过使用药物，使患者能够重新获得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.