Regulation of intra-axonal protein systhesis

描述（由申请人提供）：轴突隔室可以自主合成蛋白质已经被接受。这种局部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，轴突蛋白质合成是由神经损伤引发的，特别是在再生轴突中发生了强烈的蛋白质合成。这种局部蛋白质合成代表了一种可能被利用来促进成人神经系统轴突再生的机制。尽管轴突蛋白质合成具有明显的功能意义和新近增加的兴趣，但我们对这一过程是如何调控的知之甚少。我们的初步研究表明，成年人的轴突有可能合成一个复杂的群体超过200种不同的蛋白质;显然有一些特异性选择蛋白质产生的时间和地点。这个提议的目的是确定轴突蛋白质合成是如何调节的。我们假设，轴突刺激改变本地化的蛋白质合成，通过指导特定的mRNA的运输到轴突室和本地控制的轴突翻译机器的活动。在目标1中，我们将确定轴突导向线索和生长促进刺激如何改变轴突蛋白合成的特异性。将针对所鉴定的每种轴突合成蛋白确定轴突运输与局部合成的贡献。这些蛋白质在轴突生长的局部合成的生理后果将得到解决。在目标2中，我们将探讨轴突如何控制细胞器和膜蛋白的合成，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。最近已经认识到，受损的神经过程能够产生它们自己的蛋白质。我们的研究表明，这可能是用来提高神经系统损伤后的恢复。这项资助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。

DESCRIPTION (provided by applicant): 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 axonal translational 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.