Cellular Dynamics of Axon Regeneration

轴突再生的细胞动力学

基本信息

批准号：
10630939
负责人：
Andrew D Chisholm
金额：
$ 44.4万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630939
关键词：
Adult Aging Animals Axon Biological Models Biological Process Caenorhabditis elegans Cells Complex Data Development Drosophila genus Environment FRAP1 gene Family Gene Expression Regulation Genes Genetic Models Genetic Screening Goals Growth Growth Inhibitors Human Individual Injury Knowledge Link Maintenance Mediating Mitochondria Modeling Molecular Natural regeneration Nervous System Neurons Organism PTEN gene Pathway interactions Peripheral Nerves Phosphorylation Phosphotransferases Play Post-Transcriptional Regulation Process Proteins Proteomics Publishing Recovery Regulation Repression Resolution Ribosomal Protein S6 Ribosomal Protein S6 Kinase Ribosomes Role Signal Transduction Tertiary Protein Structure Testing Therapeutic Transcriptional Regulation Trauma Vertebrates Work adenylate axon injury axon regeneration axonal sprouting candidate selection combinatorial gene conservation genome-wide analysis improved in vivo in vivo regeneration inhibitor innovation insight lipid metabolism loss of function mRNA Decay mRNA Differential Displays novel permissiveness regenerative repaired response response to injury ribosomal protein S6 kinase kinase screening

项目摘要

The goal of this work is to define how axons regrow and reconnect after injury, focusing on molecular regulators acting within individual axons. Our model system is the simple animal C. elegans, in which single axons can be severed and regrow in vivo in a generally permissive environment. We have used large-scale genetic screens to discover conserved genes that promote or repress axon regrowth, most of which are not involved in developmental axon outgrowth. We propose to examine in depth the roles and interactions of three new regrowth-inhibiting pathways revealed from screening. First, we will dissect the roles of a conserved regulator of axonal sprouting that may regulate neuronal lipid metabolism. Second, we will examine how a highly conserved kinase pathway inhibits axon regrowth. Finally, we will elucidate the role of mRNA decay regulators in axonal regrowth and their potential link to mitochondrial function. Results from this work will elucidate intrinsic mechanisms that allow mature axons to respond to injury and regrow after damage. In vertebrates, peripheral nerves are capable of regrowth, yet recovery after peripheral nerve trauma is often slow and incomplete. The human 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 in organisms with high intrinsic regrowth capacity will also inform our understanding of why CNS neurons do not regrow. Many C. elegans pathways have been found to have conserved roles in axon regrowth, indicating the mechanisms underlying C. elegans axon regrowth will continue to yield insights into general principles of neuronal repair.

这项工作的目的是定义轴突在受伤后如何重新生长和重新连接，集中精力关于作用在单个轴突内的分子调节剂。我们的模型系统是简单的动物C.秀丽隐杆线虫，其中可以切断单轴突并在体内再生通常允许的环境。我们已经使用了大规模的遗传筛选发现促进或抑制轴突再生的保守基因，其中大多数不是参与发育轴突的生长。我们建议深入研究角色筛选揭示的三种新的抑制途径的相互作用。首先，我们将剖析可能的轴突发芽调节剂的作用调节神经元脂质代谢。其次，我们将研究如何保守激酶途径抑制轴突再生。最后，我们将阐明mRNA衰变的作用轴突再生的调节剂及其与线粒体功能的潜在联系。结果这项工作将阐明固有机制，使成熟的轴突能够做出响应伤害后的伤害和再生。在脊椎动物中，周围神经能够再生，但外周神经创伤后的恢复通常很慢且不完整。这人类中枢神经系统在受伤后经历最少的再生，反映了综合效应抑制环境和内在的再生能力降低。改进具有高内在再生能力的生物体中的再生机制知识还将告知我们对CNS神经元为什么不重生的理解。许多秀丽隐杆线虫已经发现途径在轴突再生中具有保守的作用，表明秀丽隐杆线虫轴突再生的机制将继续产生洞察力神经元修复的一般原则。