Regulation of axonal proteins synthesis

轴突蛋白质合成的调节

• 批准号: 7575163
• 负责人: JEFFERY L TWISS
• 金额: $ 32.02万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575163
• 关键词: Address; Adult; Amino Acids; Applications Grants; Attenuated; Axon; Axonal Transport; Carrier Proteins; Cell surface; Complex; Confocal Microscopy; Cues; Detection; Distal; Genetic Translation; Goals; Golgi Apparatus; Growth; Individual; Injury; Internal Ribosome Entry Site; Label; Mediating; Membrane Proteins; Messenger RNA; Methodology; Methods; Molecular Chaperones; Natural regeneration; Nerve; Nerve Regeneration; Nervous System Trauma; Nervous system structure; Neurons; Organelles; Pathway interactions; Physiological; Population; Process; Protein Biosynthesis; Proteins; Proteomics; Publications; Recovery; Regulation; Research Personnel; Resolution; Role; Running; Sensory; Signal Transduction; Source; Specificity; Stimulus; Stress; Structure; Transcript; Translational Regulation; Translations; Work; axon growth; axon regeneration; axonal guidance; axonal pathfinding; base; cDNA Arrays; extracellular; inhibitor/antagonist; injured; interest; nerve injury; neurotrophic factor; programs; protein transport; research study; response; trafficking

It has become accepted that the axonal compartment can autonomously synthesize proteins. This local translation provides the axon with a renewable source of proteins to respond to extracellular stimuli. Studies from the Pi's group have shown that axonal protein synthesis is triggered by neural injury and that particularly robust protein synthesis occurs in regenerating axons. This localized protein synthesis represents a mechanism that can likely be harnessed to facilitate the regeneration of axons in the adult nervous system. Despite the obvious functional significance and newly increased interests in axonal protein synthesis, we little understanding of how this process is regulated. Our preliminary studies indicate that adult axons have the potential to synthesize a complex population of more than 200 different proteins; there is clearly some specificity to choose which proteins are generated when and where. The objective of this proposal is to determine how this axonal protein synthesis is regulated. We hypothesize that axonal stimulation alters localized protein synthesis through both directing the transport of particular mRNAs into the axonal compartment and locally controlling the activity of the axonaltranslational machinery. In Aim 1, we will determine how axonal guidance cues and growth promoting stimuli modify specificity of axonal protein synthesis. The contributions of axonal transport vs. localized synthesis will be determined for each axonally synthesized protein identified. The physiological consequences of localized synthesis of these proteins in axonal growth will be addressed. In Aim 2 we will ask how the axon controls synthesis of organelle and membrane proteins and the functional relevance of these pathways to nerve regeneration. Nerve regeneration is abysmally slow and rarely successful. It has recently been recognized that injured nerve processes are capable of generating their own proteins. Our studies indicate that this may be used to enhance recovery after injury of the nervous system. The objective of this grant application is to determine how local protein synthesis in nerve processes is regulated by extracellular stimuli.

轴突隔室可以自主合成蛋白质，这一点已被公认。此本地 翻译为轴突提供了可再生的蛋白质来源，以响应细胞外刺激。 Pi的研究小组的研究表明，轴突蛋白质的合成是由神经损伤触发的， 在再生轴突中发生特别稳健的蛋白质合成。这种局部的蛋白质合成 代表了一种可能被利用来促进成年人轴突再生的机制， 神经系统尽管轴突蛋白具有明显的功能意义并且最近人们对轴突蛋白的兴趣增加 合成，我们很少了解这个过程是如何调节的。我们的初步研究表明， 成年人的轴突有潜力合成一个复杂的人口超过200种不同的蛋白质; 很明显是一些特异性来选择蛋白质在何时何地产生。的目的 这项研究的目的是确定这种轴突蛋白质合成是如何调节的。我们假设轴突 刺激通过引导特定mRNA的转运进入细胞， 轴突隔室和局部控制的轴突translational机器的活动。在目标1中， 我们将确定轴突引导线索和生长促进刺激如何改变轴突的特异性， 蛋白质合成。轴突运输与局部合成的贡献将被确定为每个 轴突合成蛋白鉴定。这些局部合成的生理后果 蛋白质在轴突生长将被解决。在目标2中，我们将询问轴突如何控制合成 细胞器和膜蛋白以及这些途径与神经再生的功能相关性。 神经再生是极其缓慢的，很少成功。最近发现，受伤 神经过程能够产生它们自己的蛋白质。我们的研究表明， 促进神经系统损伤后的恢复。本拨款申请的目的是 确定神经过程中的局部蛋白质合成如何受到细胞外刺激的调节。