Localized translation of cytoskeletal proteins in axonal morphogenesis

细胞骨架蛋白在轴突形态发生中的局部翻译

基本信息

批准号：
8661318
负责人：
GIANLUCA GALLO
金额：
$ 33.77万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661318
关键词：
Actins Address Adult Affect Animal Model Axon Biological Models Cell Adhesion Molecules Cells Cellular biology Chick Embryo Code Complex Cytoskeletal Proteins Cytoskeleton Data Development Disease Embryo Extracellular Matrix Filopodia Fluorescent in Situ Hybridization Foundations Future Genetic Translation Goals Growth Cones Image Image Analysis In Vitro Individual Investigation Joints Lead Life Link Mediating Mediator of activation protein Messenger RNA Methods Microfluidics Morphogenesis Nerve Growth Factors Nervous System Trauma Nervous system structure Neuronal Injury Neuronal Plasticity Neurons Organism Pattern Phosphatidylinositols Phosphotransferases Preparation Protein Biosynthesis Proteins Reagent Recovery of Function Regulation Reporter Reverse Transcriptase Polymerase Chain Reaction Role Semaphorin-3A Sensory Set protein Signal Transduction Small Interfering RNA Spinal Cord Synapses System Testing Therapeutic Time Translating Translations Work axon growth base experimental analysis extracellular frontier human EMS1 protein in vivo microtubule-associated protein 1B neuronal cell body novel novel strategies public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): The formation of axon collateral branches underlies the ability of neurons to make synaptic contacts with multiple target neurons and thus give rise to complex neuronal networks. In the context of nervous system injury, the formation of axon collateral branches can have either beneficial or undesired effects depending on the affected circuitry. Collateral branches are also affected by a variety of disease states. However, the cellular mechanisms of collateral branching are only minimally understood. The preliminary data presented in this proposal unveils for the first time that the branch-inducing signal nerve growth factor drives the intra-axonal synthesis of cytoskeletal proteins with roles in the formation of collateral branches. Importantly, the preliminary data also demonstrate that axonal protein synthesis is required for the induction of axon collateral branching by nerve growth factor. Although recent studies have revealed a large set of mRNAs targeted to axons, the functional roles of the axonal translation of axonal mRNAs remains minimally understood. The main aim of the proposal is to determine the roles of the axonal synthesis of individual cytoskeletal proteins in the formation of axon collateral branches. By bridging the expertise of the PI (Dr. Gallo; neuronal cytoskeletal cell biology) and the Co-I (Dr. Twiss; axonal protein synthesis), the project provides the unique opportunity to uncover a new aspect of the mechanism of axon branching and aims to directly link the axonal synthesis of specific cytoskeletal proteins to the regulation f the dynamics of the axonal cytoskeleton. Through the joint expertise of the PI and Co-I, the project takes a multi-pronged in vivo and in vitro approach to address the main Aims. Collateral branching is affected by nervous system injury and disease. However, the ability to manipulate branching in a therapeutic context is mostly lacking. The project has the potential to lead to strategies for the regulation of axon branching by targeting specific axonal mRNA species in the context of neuronal injury and disease. The reagents developed for use in the project (e.g., cell permeable tools to selectively inhibit the axonal translation of individual mRNA species) have the potential for translation to animal model system of collateral branching in future directions o the project. The work we propose will serve as the foundation for these long term goals by determining the relevant mRNA targets through the elucidation of their roles in branching.

描述（由申请人提供）：轴突侧支分支的形成是神经元与多个目标神经元进行突触接触并因此产生复杂神经元网络的能力的基础。在神经系统损伤的情况下，轴突侧支分支的形成可能会产生有益或不良的影响，具体取决于受影响的电路。侧枝也受到多种疾病状态的影响。然而，人们对侧枝分支的细胞机制了解甚少。该提案中提出的初步数据首次揭示了分支诱导信号神经生长因子驱动细胞骨架蛋白的轴突内合成，并在侧支分支的形成中发挥作用。重要的是，初步数据还表明，轴突蛋白质合成是神经生长因子诱导轴突侧支分支所必需的。尽管最近的研究揭示了大量针对轴突的 mRNA，但轴突 mRNA 的轴突翻译的功能作用仍然知之甚少。该提案的主要目的是确定单个细胞骨架蛋白的轴突合成在轴突侧支分支形成中的作用。通过结合 PI（Gallo 博士；神经细胞骨架细胞生物学）和 Co-I（Twiss 博士；轴突蛋白合成）的专业知识，该项目提供了揭示轴突分支机制新方面的独特机会，旨在将特定细胞骨架蛋白的轴突合成与轴突细胞骨架动力学的调节直接联系起来。通过 PI 和 Co-I 的联合专业知识，该项目采用多管齐下的体内和体外方法来实现主要目标。侧支分支受神经系统损伤和疾病的影响。然而，在治疗环境中操纵分支的能力大多缺乏。该项目有可能通过在神经元损伤和疾病的背景下针对特定的轴突 mRNA 种类来制定调节轴突分支的策略。为该项目开发的试剂（例如，选择性抑制单个 mRNA 种类的轴突翻译的细胞渗透工具）有可能在该项目的未来方向上转化为侧支分支的动物模型系统。我们提出的工作将通过阐明相关 mRNA 靶标在分支中的作用来确定它们，从而为这些长期目标奠定基础。