Activation of critical gene sets for spinal axon repair

激活脊髓轴突修复的关键基因组

• 批准号: 6604061
• 负责人: J H PATE SKENE
• 金额: $ 23.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604061
• 关键词: axon; denervation; gene induction /repression; genetically modified animals; growth cones; laboratory mouse; laboratory rat; microarray technology; nervous system regeneration; neurogenetics; proteomics; spinal cord injury

DESCRIPTION (provided by applicant): In order to restore connections interrupted by spinal cord injury, adult neurons must carry out modes of axon extension more typical of developing cells. Many adult neurons, however, are known to be deficient in at least some of the protein components of axonal growth cones, which mediate axon extension and guidance. Successful regeneration appears to require re-expression of these and other proteins, but it is not known which growth cone components are expressed in spinal projection neurons after spinal cord injury. The current proposal is to develop a global gene expression assay that can be used to monitor the activation of a program of gene expression adequate to support axon regeneration and functional repair following spinal cord injury. The first stage of the work will use a large cDNA microarray to compare the changes in neuronal gene expression induced by spinal cord injury and by peripheral nerve damage (which elicits robust axon regeneration and functional recovery). The second aim is to determine which of these responses to axon injury reflect the activation of genes involved in axon regeneration, rather than the onset of cell death or stress responses. This analysis will employ two parallel approaches. A correlational cluster analysis of microarray data will be used to identify sets of genes most closely correlated with axon growth, while a "proteomics" profile of growth cone proteins will be used to determine which genes induced by axotomy represent the expression of proteins directly involved in axon growth. The results will show whether spinal projection neurons ordinarily initiate an effective genetic program for axon regrowth following spinal cord injury, or remain deficient in particular growth cone components. Moreover, they will establish a "molecular profile" that can be used to distinguish the modes of action of treatments designed to enhance spinal cord repair. We will test the feasibility of using this profile to determine which treatments act by stimulating neuronal genes involved in axon regrowth, and which treatments act by improving the growth-supporting properties of the spinal cord environment. Together, the proposed studies address one of the fundamental hurdles to spinal axon regeneration, and provide a tool for evaluating therapeutic strategies for spinal cord repair.

描述（由申请人提供）： 为了恢复因脊髓损伤中断的连接，成人 神经元必须执行更典型的轴突扩展模式 细胞。但是，许多成年神经元至少在某些中缺乏 轴突生长锥的蛋白质成分，介导轴突延伸 和指导。成功的再生似乎需要重新表达这些 和其他蛋白质，但尚不清楚哪些生长锥成分是 脊髓损伤后在脊柱投射神经元中表达。电流 建议是开发一个可以用来用于的全球基因表达测定法 监视足够支持轴突的基因表达程序的激活 脊髓损伤后的再生和功能修复。第一个 工作阶段将使用大型cDNA微阵列来比较 由脊髓损伤和周围神经诱导的神经元基因表达 损坏（这会引起稳健的轴突再生和功能恢复）。这 第二个目的是确定哪些对轴突损伤的反应反映了 激活轴突再生的基因，而不是开始 细胞死亡或压力反应。该分析将采用两个平行 方法。微阵列数据的相关群集分析将用于 确定与轴突生长最紧密相关的基因集，而 生长锥蛋白的“蛋白质组学”概况将用于确定哪个 轴突切开术诱导的基因表示蛋白质的表达直接涉及 在轴突生长中。结果将显示脊柱投射神经元是否 通常启动有效的遗传程序，以进行轴突再生 脊髓损伤或在特定生长锥体成分中保持不足。 此外，它们将建立一个可以用来用于的“分子剖面” 区分旨在增强脊髓的治疗方法的作用模式 维修。我们将测试使用此配置文件确定哪个配置文件的可行性 通过刺激参与轴突再生的神经元基因和 哪种治疗方法通过改善了生长支持的特性 脊髓环境。拟议的研究一起解决了其中一项 脊柱轴突再生的基本障碍，并为 评估脊髓修复的治疗策略。