Coupled axonal protein synthesis and lipidation in axon growth and homeostasis

轴突生长和稳态中的耦合轴突蛋白合成和脂化

基本信息

批准号：
10056229
负责人：
Rejji Kuruvilla
金额：
$ 43.28万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056229
关键词：
Acute Address Adult Affect Attenuated Axon Biochemical Biochemistry Caliber Carbon Cell physiology Cells Cellular Structures Coupled Couples Coupling Cues Cytoplasm Development Distal Endosomes Ensure Environment Enzymes Goals Growth Growth Cones Homeostasis Image Injury Knowledge Length Life Link Lipids Maintenance Measures Mediating Messenger RNA Modification Monitor Monomeric GTP-Binding Proteins Morphology Mus NGFR Protein Natural regeneration Nerve Growth Factors Neurons Pharmacology Phosphorylation Presynaptic Terminals Process Protein Biosynthesis Protein Geranylgeranylation Protein Inhibition Protein Isoprenylation Proteins RNA Regulation Role Signal Transduction Sympathetic Ganglia Testing Tissues Transferase Translations axon growth experimental study geranylgeranylation improved in vivo mouse genetics mutant nerve repair nerve supply neurotrophic factor novel therapeutics polarized cell prenyl prenylation protein expression protein function recruit repaired response spatiotemporal trafficking

项目摘要

Axons continuously respond to external signals in their environment as they grow and navigate toward their target tissues during development, and for maintenance and repair in adult life. mRNA localization and local protein synthesis is a conserved mechanism that allows for rapid and axon-autonomous responses to external trophic and guidance cues. Despite growing appreciation for the functions of axonal protein synthesis, a major gap in our knowledge is in understanding how the nascent proteins are further processed and localized in axons to generate fully functional proteins. Our preliminary results suggest that a neurotrophic factor (Nerve Growth Factor) acutely regulates local protein synthesis and lipidation (prenylation) of newly-made proteins in axons. It has been assumed that protein prenylation is a constitutive mechanism that occurs throughout the cytoplasm and is permissive for cellular functions. In striking contrast, we find that, in neurons, prenylation is under exquisite spatio-temporal control by extrinsic signals. The goal of this application is to define whether coupled axonal protein synthesis and prenylation serves as a regulatory mechanism to localize and enrich proteins in axonal compartments to ensure dynamic and spatial responses to extrinsic growth-promoting cues. We will use a combination of imaging, biochemical, and functional analyses in compartmentalized neuronal cultures, as well as in vivo analyses in mice to accomplish this goal. These studies will advance the knowledge of spatial modes of signaling in neurons that underlie axon development, maintenance, and regeneration.

轴突在成长时不断响应其环境中的外部信号，在开发过程中驶向目标组织，并进行维护和维修在成人生活中。 mRNA定位和局部蛋白质合成是一种保守机制，允许对外部营养和指导提示产生快速和轴突自治的反应。尽管人们对轴突蛋白合成功能的增强越来越多，但仍有一个主要差距我们的知识在于了解如何进一步处理新生蛋白质以及位于轴突中以生成功能齐全的蛋白质。我们的初步结果表明神经营养因子（神经生长因子）急性调节局部蛋白质合成轴突中新制造的蛋白质的脂质化（前化）。已经假定蛋白质前化是一种构成机制，在整个细胞质中发生，具有细胞功能的允许性。在引人注目的对比中，我们发现，在神经元中，原化原化通过外在信号在精美的时空控制下。该应用程序的目标是定义偶联的轴突蛋白合成和原始化是否作为A 调节机制，以定位和富集轴突室中的蛋白质，以确保对外在生长提示的动态和空间反应。我们将使用一个成像，生化和功能分析的组合神经元文化以及体内分析小鼠以实现这一目标。这些研究将促进对神经元信号的空间模式的了解，而神经元的基础轴突开发，维护和再生。