B-RAF drives regenerative axon growth in the optic nerve in vivo

B-RAF 驱动体内视神经再生轴突生长

基本信息

批准号：
8658099
负责人：
Jian Zhong
金额：
$ 44.35万
依托单位：
WINIFRED MASTERSON BURKE MED RES INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658099
关键词：
1-Phosphatidylinositol 3-Kinase Address Adult Afferent Neurons Alleles Axon Biological Assay Cell Nucleus Cells Collaborations Data Degenerative Disorder Development Drug Targeting Embryo Failure Future Genetic Recombination Glaucoma Goals Growth Image Injury Institutes Knock-out MAP Kinase Modules MAP2K1 gene MAPK1 gene MAPK3 gene MEKs Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Mus Natural regeneration Nerve Crush Nervous System Trauma Neuraxis Neurites Neurons Optic Nerve Optic Nerve Injuries Optic tract structure PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Procedures Proteins Proto-Oncogene Proteins c-akt Public Health Recovery Recovery of Function Rehabilitation therapy Retina Retinal Ganglion Cells Role Sensory Serum Response Factor Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Tamoxifen Testing Time Translational Research Trauma Vision axon growth axon regeneration base central nervous system injury disability gain of function improved in vivo injured loss of function mouse model neurotrophic factor novel novel strategies optic nerve regeneration prevent regenerative research study retinal axon small hairpin RNA two-photon vector

项目摘要

DESCRIPTION (provided by applicant): Injured axons in the mature central nervous system (CNS), including the optic nerve, cannot regenerate spontaneously. This inability to regenerate causes permanent disability after CNS injuries. A better understanding of the impediments to axon regeneration, and novel approaches towards overcoming them, are necessary for the development of new drugs and procedures that may improve the fate of patients with nervous system injury in the future. Our goal is to enable CNS axon regeneration by elevating intrinsic growth signaling. The RAF kinase is known to drive fast axon growth in embryonic sensory neurons; we therefore will now activate this kinase in the retina. Our first aim is to promote regeneration in the injured optic nerve using a conditional B-RAF gain-of-function mouse model. We will then test the roles of signaling molecules downstream of RAF signaling - the MEKs, ERKs and RNDs - for their contributions to B-RAF-driven retinal axon regeneration (Aim 2). Next, we plan to combine activation of B-RAF with activation of PI3-kinase signaling (using a knock-out of the PI3-kinase antagonist PTEN) to see whether this combination will further boost regenerative optic nerve axon growth in vivo (Aim 3). If we can observe regeneration into any of the optic tract nuclei, we will test the mice for any recovery of visual function; such functional recovery being the ultimate goal of all axon regeneration studies. The proposed study will define the roles of RAF signaling and its downstream effectors in the context of optic nerve regeneration, laying groundwork for translational research and for the identification of novel drug targets.

描述（由申请人提供）：成熟中枢神经系统（CNS）（包括视神经）中受损的轴突无法自发再生。这种无法再生的情况会导致中枢神经系统损伤后永久性残疾。更好地了解轴突再生的障碍以及克服这些障碍的新方法对于开发新的药物和程序是必要的，这些新的药物和程序可能会改善未来神经系统损伤患者的命运。我们的目标是通过增强内在生长信号来实现中枢神经系统轴突再生。已知 RAF 激酶可驱动胚胎感觉神经元的轴突快速生长；因此，我们现在将激活视网膜中的这种激酶。我们的首要目标是使用条件 B-RAF 功能获得性小鼠模型促进受损视神经的再生。然后，我们将测试 RAF 信号下游信号分子（MEK、ERK 和 RND）的作用，以了解它们对 B-RAF 驱动的视网膜轴突再生的贡献（目标 2）。接下来，我们计划将 B-RAF 的激活与 PI3 激酶信号传导的激活结合起来（使用 PI3 激酶拮抗剂 PTEN 的敲除），看看这种组合是否会进一步促进体内视神经轴突再生生长（目标 3））。如果我们能够观察到任何视神经核的再生，我们将测试小鼠视觉功能的恢复情况；这种功能恢复是所有轴突再生研究的最终目标。拟议的研究将定义 RAF 信号传导及其下游效应器在视神经再生中的作用，为转化研究和新药鉴定奠定基础目标。