Repair and Regeneration of Central Visual Pathways

中央视觉通路的修复和再生

• 批准号: 7018505
• 负责人: BEN A BARRES
• 金额: $ 39.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-01-22 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018505
• 关键词: amacrine cells; astrocytes; axon; denervation; developmental neurobiology; gene expression; laboratory rat; macrophage; microarray technology; microglia; myelin; nerve /myelin protein; nerve injury; nervous system regeneration; neutralizing antibody; optic nerve; peptide library; phagocytosis; polymerase chain reaction; retinal ganglion; tissue /cell culture; visual pathways; wallerian degeneration

DESCRIPTION (provided by applicant): We propose to investigate why central visual pathways fail to regenerate after injury and how their repair can be enhanced. Specifically, we will investigate why the axons of mature retinal ganglion cells (RGCs) fail to regenerate after axotomy. The regeneration of RGCs through the optic nerve has long served as a simple model system for study of CNS regenerative failure. The rat optic nerve consists primarily of RGC axons, astrocytes, and myelinating oligodendrocytes. We have developed methods to purity and culture rodent RGCs, optic nerve astrocytes and oligodendrocytes. Using these methods we will continue to investigate the molecular mechanisms that promote and inhibit RGC axon elongation in culture, and how we can apply this knowledge to enhance regeneration. In this proposal, we will investigate the molecular basis of 3 phenomena implicated in the failure of RGC axons to regenerate. Over the last grant period, we discovered that neonatal RGCs are signaled by amacrine cells to irreversibly lose their intrinsic competence to rapidly regenerate their axons. In the first aim, we will use gene profiling to investigate the molecular basis for this loss. In the second aim, we investigate the identity of myelin-associated inhibitors of regeneration in the optic nerve and the RGC receptors that they bind to by constructing bacteriophage display libraries of single chain antibodies and selecting antibodies that enhance RGC regeneration. In the third am, we will investigate why the clearance of myelin debris in Wallerian degeneration is so prolonged after optic nerve injury. We will specifically test the hypothesis that this is accounted for by the recent discovery that CNS microglia are immature myeloid precursor cells rather than quiescent phagocytes. Finally, we will apply what we learn in the first 3 aims to determine if we can enhance RGC regeneration after optic nerve injury in vivo. Our ultimate goal is to understand why RGCs fail to regenerate afar axotomy and to develop new treatments promote their regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis, and neuropathy.

描述(由申请人提供)：我们建议调查为什么中央视觉通路在损伤后不能再生，以及如何加强它们的修复。具体地说，我们将调查为什么成熟的视网膜神经节细胞(RGC)的轴突在轴突切断后不能再生。长期以来，视神经再生视网膜节细胞一直是研究中枢神经系统再生衰竭的简单模型系统。大鼠视神经主要由RGC轴突、星形胶质细胞和髓鞘少突胶质细胞组成。我们已经建立了纯化和培养啮齿动物视网膜神经节细胞、视神经星形胶质细胞和少突胶质细胞的方法。使用这些方法，我们将继续研究在培养中促进和抑制RGC轴突延长的分子机制，以及我们如何应用这些知识来促进再生。 在这个方案中，我们将研究与RGC轴突再生失败有关的三个现象的分子基础。在上一次授予期间，我们发现新生视网膜节细胞由无长突细胞发出信号，不可逆转地失去其迅速再生轴突的内在能力。在第一个目标中，我们将使用基因图谱来研究这种丢失的分子基础。在第二个目的中，我们通过构建单链抗体的噬菌体展示文库和选择促进RGC再生的抗体来研究视神经中髓鞘相关再生抑制因子及其结合的RGC受体的身份。在第三个上午，我们将调查为什么瓦勒变性的髓鞘碎片在视神经损伤后清除如此长的时间。我们将专门测试这一假设，即这是由最近发现的CNS小胶质细胞是未成熟的髓样前体细胞而不是静止的吞噬细胞所解释的。最后，我们将应用我们在前三个目标中学到的东西来确定我们是否可以在体内促进视神经损伤后的RGC再生。 我们的最终目标是了解视网膜神经节细胞无法在远端轴突切断后再生的原因，并开发新的治疗方法促进其在青光眼、视网膜缺血、视神经炎和神经病等眼科疾病中的再生。