MICROTUBULE POST-TRANSLATIONAL MODIFICATIONS IN AXON REGENERATION

轴突再生中的微管翻译后修饰

基本信息

批准号：
8810263
负责人：
Valeria Cavalli
金额：
$ 33.25万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8810263
关键词：
Acetylation Axon Axonal Transport Back Biological Assay Calcium Cell Nucleus Confocal Microscopy Cues Cytoskeleton Data Deacetylase Deacetylation Electron Microscopy Environment Enzymes Event Future Goals Growth Growth Cones HDAC5 gene Health Histone Deacetylase Injury JNK-activating protein kinase Laboratories Lesion MAPK8 gene Maintenance Measures Mediating Microtubules Modification Molecular Morphology Natural regeneration Nervous System Physiology Neuraxis Neurobiology Neurons Nuclear Export Pathway interactions Peripheral Peripheral Nervous System Play Post-Translational Protein Processing Problem Solving Process Property Recovery Regenerative response Role Signal Pathway Signal Transduction Site Structure Testing Therapeutic Intervention Time Tubulin Vesicle axon injury axon regeneration central nervous system injury extracellular injured insight knock-down mouse model mutant nerve injury neuronal cell body new growth novel programs regenerative research study response retrograde transport small hairpin RNA tyrosyltubulin ligase

项目摘要

DESCRIPTION (provided by applicant): Lack of robust axonal regeneration represents one of the major barriers to recovery of neurological functions following injury to neurons within the central nervous system (CNS). In contrast, neurons in the peripheral nervous system (PNS) have a remarkable ability to regenerate after injury. The extent of axonal regeneration not only depends on the presence or absence of inhibitory cues in the environment, but also on the intrinsic growth capacity of damaged neurons. Indeed, blocking extracellular inhibitory influences alone is not sufficient to allow complete axon regeneration, emphasizing the need for a better understanding of the mechanisms controlling the intrinsic regenerative ability of injured neurons. The mechanisms that govern axon regeneration operate both in the cell body and locally in the axon. The local axonal responses allow injured neurons to signal back to the cell body and to transform their damaged axonal tips into a new growth- cone-like structure, two processes that are essential to initiate regeneration. In pursuing our studies on the response of axons to injury, we recently focused on the microtubule (MT) cytoskeleton. We found that the histone deacetylase HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. HDAC5 accumulates and deacetylates tubulin at the tip of injured PNS, but not CNS axons. HDAC5-mediated tubulin deacetylation is essential for PNS neuron's ability to regenerate, but fails to occur in CNS neurons. In addition to tubulin deacetylation, we observed that PNS axon injury also increases tubulin tyrosination. Tubulin acetylation and tyrosination are known to contribute to the dynamics properties of MTs and to MT-dependent axonal transport. However, the signaling pathways elicited by injury, which regulate MT posttranslational modifications and the precise role these modifications play in axon regeneration remain elusive. Here we propose to uncover the mechanisms controlling MT post-translational modifications in injured axons and to establish their specific roles in injured axons. Specifically, we will determine how a tubulin deacetylation gradient is maintained over time to sustain axon regeneration. We will also determine whether tubulin tyrosination initiates the retrograde transport of injury signals to activate a pro- regenerative program. Our long-term goal is to gain new insights into the molecular events that dictate the regenerative response of PNS neurons, and identify potential targets for future therapeutic interventions in the setting of CNS injury.

描述（由申请人提供）：缺乏健壮的轴突再生是中枢神经系统（CNS）内神经元后神经功能恢复的主要障碍之一。相反，外周神经系统（PNS）中的神经元具有显着的受伤后再生能力。轴突再生的程度不仅取决于环境中抑制性线索的存在，还取决于受损神经元的内在生长能力。实际上，仅阻止细胞外抑制性影响不足以允许完全轴突再生，强调需要更好地理解控制受伤神经元内在再生能力的机制。控制轴突再生的机制在细胞体和轴突局部起作用。局部轴突反应使受伤的神经元可以向细胞体发出信号，并将其受损的轴突尖转换为新的生长锥状结构，这是引发再生必不可少的两个过程。在追求有关轴突对损伤的反应的研究时，我们最近专注于微管（MT）细胞骨架。我们发现组蛋白脱乙酰基酶HDAC5是一种新型损伤调节的微管蛋白脱乙酰基酶控制轴突再生。 HDAC5在受伤的PNS的尖端累积并脱乙酰基小管蛋白，而不是CNS轴突。 HDAC5介导的小管蛋白脱乙酰基化对于PNS神经元的再生能力至关重要，但在中枢神经系统神经元中未能发生。除了微管蛋白脱乙酰化外，我们还观察到PNS轴突损伤还增加了微管蛋白硫化。众所周知，微管蛋白乙酰化和硫化有助于MT的动力学特性和MT依赖性轴突转运。然而，受伤引起的信号传导途径调节MT翻译后修饰以及这些修饰在轴突再生中的确切作用仍然难以捉摸。在这里，我们建议揭示控制MT轴突翻译后修饰的机制，并在受伤的轴突中确定其特定作用。具体而言，我们将确定如何随着时间的推移维持微管蛋白脱乙酰化梯度以维持轴突再生。我们还将确定小管蛋白硫化是否会引发伤害信号的逆行运输以激活促进程序。我们的长期目标是获得对决定PNS神经元再生反应的分子事件的新见解，并在中枢神经系统损伤的情况下确定未来治疗干预措施的潜在靶标。