Guidance of Oligodendrocyte Processes: The Role of Local Protein Synthesis

少突胶质细胞过程的指导：局部蛋白质合成的作用

• 批准号: 7210043
• 负责人: BABETTE FUSS
• 金额: $ 19.56万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210043
• 关键词: Address; Axon; Cell physiology; Cells; Characteristics; Code; Condition; Cues; Data; Data Set; Demyelinating Diseases; Development; Distal; Goals; Growth Cones; Human; Individual; Individuality; Knowledge; Lesion; Mediating; Membrane; Messenger RNA; Molecular; Morphology; Multiple Sclerosis; Myelin Sheath; Neuraxis; Neurites; Neurons; Oligodendroglia; Organelles; Patients; Personal Satisfaction; Process; Protein Biosynthesis; Protein Inhibition; Protein Synthesis Inhibition; Proteins; Regulation; Role; Set protein; Signal Transduction; Staging; Stimulus; Structure; Testing; Therapeutic; Translations; base; design; extracellular; insight; interest; myelination; neuronal cell body; neuronal growth; novel; repaired; research study; response; synaptogenesis

DESCRIPTION (provided by applicant): During development of the central nervous system (CNS) post-migratory cells of both neuronal and oligodendroglial origin send out processes that navigate through the parenchyma in search for a target signal that induces their maturation, i.e. synapse formation for neuronal and myelin sheath formation for oligodendroglial cells. The regulation of this process navigation has been well characterized for neuronal cells, where a sensorimotor structure, the neuronal growth cone, located at the process tip is the "organelle" that senses environmental cues. In contrast, surprisingly little is known about oligodendroglial process pathfinding and targeting. Our preliminary data demonstrate that oligodendrocyte processes possess at their distal ends "organelles" that structurally and functionally resemble neuronal growth cones and that we will refer to as oligodendroglial growth cone-like structures (OLG-growth cones). In neurons, mRNA transport and locally restricted protein synthesis within the growth cone are considered main regulators of axon/neurite pathfinding and targeting. Our preliminary data suggest that similar regulatory mechanisms may be important for the pathfinding and targeting of oligodendrocyte processes. Thus, we formulate the central hypothesis that premyelinating, post-migratory oligodendrocytes possess OLG-growth cones that contain mRNAs, the locally restricted translation of which is critical for the regulation of oligodendroglial process pathfinding and targeting, i.e. myelination. This hypothesis will be tested in two specific aims. 1) We will determine the role of locally restricted protein synthesis for OLG-growth cone pathfinding and in particular for chemotropic turning in response to non-permissive cues. In this set of experiments the extent to which locally restricted protein synthesis occurs in pathfinding OLG-growth cones will be determined. In addition, chemotropic turning of separated processes will be analyzed after inhibition of protein synthesis. It is expected that inhibition of locally restricted protein synthesis will perturb OLG- growth cone chemotropic turning responses. 2) Using a microarray approach, we will identify mRNAs that are present in OLG-growth cones specifically in response to axonal targeting signals. This set of experiments is expected to reveal candidate proteins that are important for OLG-growth cone targeting, i.e. the initiation of myelin sheath formation. In continuing studies based on the findings of the present proposal, we are planning to further characterize these proteins. The proposed studies thus represent a first step into a set of experiments designed to better understand the regulation of oligodendrocyte process pathfinding and targeting. Such advancement in knowledge is of particular interest since deficiencies in process outgrowth and axon recognition appear to be among the main limiting factors for repair of lesions present in the CMS of patients suffering from the major demyelinating disease in humans, Multiple Sclerosis.

描述(申请人提供)：在中枢神经系统(CNS)的发育过程中，神经元和少突胶质起源的迁移后细胞发出穿过实质的过程，寻找诱导它们成熟的目标信号，即神经元的突触形成和少突胶质细胞的髓鞘形成。这一过程导航的调节已经被很好地表征为神经细胞，其中位于突起尖端的感觉运动结构，神经元生长锥是感觉环境线索的“细胞器”。相比之下，令人惊讶的是，对少突胶质细胞突起的寻路和靶向知之甚少。我们的初步数据表明，少突胶质细胞突起的远端具有在结构和功能上类似神经元生长锥体的“细胞器”，我们将其称为少突胶质胶质生长锥样结构(OLG-Growth Cones)。在神经元中，生长锥内的mRNA转运和局部限制的蛋白质合成被认为是轴突/轴突寻路和靶向的主要调节因素。我们的初步数据表明，类似的调控机制可能对发现和靶向少突胶质细胞突起很重要。因此，我们提出了一个中心假设，即髓鞘形成前、迁移后的少突胶质细胞具有含有mRNAs的OLG生长锥体，其局部限制性的翻译对于调控少突胶质细胞的寻路和靶向至关重要，即髓鞘形成。这一假设将在两个具体目标上得到检验。1)我们将确定局部限制的蛋白质合成在寻找OLG生长锥途径中的作用，特别是在响应非允许线索的趋化转变中的作用。在这一组实验中，将确定在寻找途径的OLG生长锥体中局部限制蛋白质合成的程度。此外，还将分析在抑制蛋白质合成后分离的过程的趋化性转变。预计抑制局部限制的蛋白质合成将扰乱OLG生长锥趋化转向反应。2)使用微阵列方法，我们将识别存在于OLG生长锥体中的mRNAs，这些mRNAs专门响应轴突靶向信号。这组实验有望揭示对OLG生长锥靶向，即髓鞘形成的启动至关重要的候选蛋白质。在基于本提案结果的持续研究中，我们计划进一步确定这些蛋白质的特征。因此，拟议的研究代表了一系列实验的第一步，这些实验旨在更好地了解少突胶质细胞过程的调控、寻径和靶向。这种知识的进步特别令人感兴趣，因为突起生长和轴突识别方面的缺陷似乎是修复患有人类主要脱髓鞘疾病-多发性硬化症患者CMS中病变的主要限制因素之一。