Cytoskeletal dynamics in axon regeneration

轴突再生中的细胞骨架动力学

基本信息

批准号：
9108446
负责人：
Andrew D Chisholm
金额：
$ 33.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108446
关键词：
Address Adult Affect Anatomy Animal Model Animals Axon Axotomy Binding Proteins Biochemical Caenorhabditis elegans Cell membrane Cytoskeleton Data Defect Development Disease Environment Exocytosis Funding Genes Genetic Genetic Models Genetic Screening Goals Growth Cones Health Human Injury Knowledge Lasers Life Light MAP Kinase Kinase Kinase Membrane Protein Traffic Microtubule-Associated Proteins Microtubules Minus End of the Microtubule Modeling Molecular Natural regeneration Nematoda Nervous system structure Neuronal Injury Neurons Pathway interactions Peripheral Nerves Phosphotransferases Play Process Protein Isoforms RNA-Binding Proteins Recovery Regulation Regulatory Pathway Role Signal Pathway Site Synapses Synaptic Vesicles Testing Trauma Vertebrates Work axon injury axon regeneration base combinatorial genetic analysis improved in vivo inhibitor/antagonist loss of function mutant new growth novel regenerative repaired response to injury sensor syntaxin syntaxin 1 target SNARE proteins

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to use the genetically tractable model organism C. elegans to dissect the molecular basis of axon regeneration after injury. The small size, transparent body, and simple anatomy of C. elegans allows single axons to be severed in vivo and their regrowth studied in depth. In the prior funding period we used large- scale genetic screens in C. elegans to discover conserved genes and pathways that play regrowth-promoting or regrowth-inhibiting roles in vivo. Many of these pathways are distinct from those involved in developmental axon outgrowth. Our large scale screens and analyses of genetic interactions have led to models for the function of these regrowth factors that we will test mechanistically in this proposal. We will dissect a signaling pathway that inhibits axon regrowth via axonal microtubule dynamics. We will investigate the role of membrane trafficking regulators in axon extension. Results from this work will elucidate intrinsic mechanisms that allow mature axons to regrow after damage. In vertebrates, peripheral nerves are capable of regrowth, yet recovery after peripheral nerve trauma is often slow and incomplete. The mammalian CNS undergoes minimal regeneration after injury, reflecting the combined effects of an inhibitory environment and of reduced intrinsic regrowth capacity. Improved knowledge of regrowth mechanisms will also inform our understanding of why CNS neurons do not regrow. Our work addresses intrinsic mechanisms that promote or inhibit axon regrowth, a high priority for this field. Many signaling pathways have conserved roles in axon regrowth, suggesting analysis of C. elegans axon regrowth has implications for understanding axon repair mechanisms in medically relevant situations.

描述（由适用提供）：该项目的总体目标是使用遗传上的模型有机体C.秀丽隐杆线虫在损伤后剖析轴突再生的分子基础。秀丽隐杆线虫的小尺寸，透明的身体和简单的解剖结构允许将单轴突切断在体内及其深度。在以前的资金期间，我们在秀丽隐杆线虫中使用了大规模的遗传筛选，发现构成的基因和途径，这些基因和途径在体内扮演着精致的促进或抑制了抑制作用。这些途径中的许多与辅助轴突生长有关的途径不同。我们的大规模筛选和遗传相互作用的分析已导致了这些精制因素的功能的模型，我们将在此提案中进行机械测试。我们将剖析通过轴突微管动力学抑制轴突精致的信号通路。我们将研究这项工作的膜运输结果的作用，将阐明固有机制，使成熟的轴突在损伤后进行完善。在脊椎动物中，周围神经系统能够进行改革，但是外周神经创伤后的恢复通常缓慢且不完整。哺乳动物中枢神经系统受伤后经历了最小的再生，反映了抑制环境的综合作用和内在改革能力降低。改善改革机制的知识还将告知我们对CNS神经元为什么不改革的理解。我们的工作解决了促进或抑制轴突改革的内在机制，这是该领域的高度优先事项。许多信号通路在轴突改革中具有保守的作用，表明对秀丽隐杆线虫轴突改革的分析对理解医学相关情况下的轴突修复机制具有意义。