GSK-3B/APC in developmental & regenerative axon growth

GSK-3B/APC 正在开发中

基本信息

批准号：
7418189
负责人：
WILLIAM D SNIDER
金额：
$ 32.01万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418189
关键词：
Address Adenomatous Polyposis Coli Protein Adult Alleles Axon Binding Breeding Cytoskeleton Data Development Distal Embryo Exhibits Family member Frequencies Gene Targeting Genetic Recombination Glycogen Synthase Kinase 3 Growth Cones In Vitro Knockout Mice Lesion Link Localized Mediating Mediator of activation protein Microtubules Morphology Mus Mutant Strains Mice Natural regeneration Nerve Crush Nerve Growth Factor 1 Nerve Growth Factor Pathway Nerve Regeneration Nervous system structure Neuroglia Neurons Pathway interactions Peripheral Peripheral Nerves Population Property Protein Isoforms Proteins Publishing Rate Reporter Research Personnel Role Sensory Serine Signal Pathway Signal Transduction Spinal Spinal Cord Spinal cord injury Tamoxifen Testing Trigeminal System Wild Type Mouse axon growth axon regeneration glycogen synthase kinase 3 beta in vitro Model in vivo integrin-linked kinase member nervous system development neurotrophic factor null mutation preconditioning programs relating to nervous system transcription factor upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Links between neurotrophin signals that regulate neuronal morphology and the neuronal cytoskeleton have remained elusive. In vitro, we have identified a pathway downstream of NGF involving spatially localized PI3K and GSK-3b signaling and binding of the Adenomatous Polyposis Coli protein (APC) to microtubule + ends at the growth cone. We hypothesize that this pathway mediates microtubule assembly during NGF induced axon growth. Both APC and GSK-3b are also strikingly localized to the distal axon tips and growth cones of rapidly growing axons of "precondition lesioned" DRG neurons in vitro. Thus we hypothesize the GSK-3b/APC pathway mediates microtubule assembly in regenerative axon growth as well. In vivo functions of GSK-3b and APC related to nervous system development have not yet been explored because of embryonic lethality in gene targeted mice and because each has a related family member also heavily expressed in the mammalian nervous system that may have a "compensatory" function. We plan to address in vivo roles of these proteins in the current proposal. We will generate inducible, DRG-specific knock-outs for GSK-3a, GSK-3b, APC, APC-L, and an upstream kinase, ILK. Using DRG specific axonal reporter mice, we will determine the roles of the GSK-3b/APC pathway in the development of peripheral and spinal cord DRG projections and in the axon regeneration normally induced by a peripheral nerve crush. If GSK-3b and APC are found to be required for assembly of microtubules during axon regeneration in vivo, and if key upstream regulators can be identified, our studies would provide a new pharmacological approach to enhancing axon regeneration after injur

描述（由申请人提供）：调节神经元形态的神经营养蛋白信号与神经元细胞骨架之间的联系仍然难以捉摸。在体外，我们已经确定了NGF下游的一条途径，该途径涉及空间定位的PI3K和GSK-3B信号传导以及腺瘤多息护物蛋白（APC）与微管 +在生长锥处的结合。我们假设该途径在NGF诱导的轴突生长过程中介导了微管组装。 APC和GSK-3B都在体外的“前提病变” DRG神经元的快速生长轴突的远端轴突尖端和生长锥上都有明显的位置。因此，我们假设GSK-3B/APC途径也介导了再生轴突生长中的微管组件。 GSK-3B和APC与神经系统发育相关的体内功能尚未探索，因为基因靶向小鼠的胚胎致死性，并且因为每个人都有一个相关的家庭成员在哺乳动物神经系统中也大量表达，而这些家庭成员可能具有“补偿性”功能。我们计划在当前提案中解决这些蛋白质的体内角色。我们将为GSK-3A，GSK-3B，APC，APC-L和上游激酶生成可诱导的DRG特异性敲除。使用DRG特异性轴突报告基因小鼠，我们将确定GSK-3B/APC途径在外围和脊髓DRG投影的发展以及通常由外围神经挤压引起的轴突再生中的作用。如果在体内轴突再生过程中发现了GSK-3B和APC需要微管组装，并且如果可以确定关键的上游调节剂，我们的研究将为增强轴突再生提供新的药理方法