REPAIR AND REGENERATION OF CENTRAL VISUAL PATHWAYS

中央视觉通路的修复和再生

• 批准号: 2020031
• 负责人: BEN A BARRES
• 金额: $ 35.1万
• 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 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2020031
• 关键词: apoptosis; brain electrical activity; cell cell interaction; cell death; cell growth regulation; laboratory rat; myelination; nerve injury; nervous system regeneration; neurotrophic factors; oligodendroglia; optic nerve; retinal ganglion; superior colliculus; tissue /cell culture

DESCRIPTION (author's): We propose to investigate why central visual pathways fail to regenerate after injury and how their repair can be enhanced. We will focus on the mechanisms that normally control the survival and growth of retinal ganglion cells (RGCs) and their axons, as well as the properties of adult oligodendrocyte precursor cells, the suspected source of new oligodendrocytes after injury. The rat optic nerve, which consists mainly of retinal ganglion cell axons and myelinating oligodendreocytes, will be used as a model system. The survival of RGCs and their axons is normally controlled by peptide signals, such as brain-derived neurotrophic factor (BDNF), that are released by neighboring cells--tectal target neurons, optic nerve astrocytes and oligodendrocytes--and retrogradely transported to the cell soma. When RGC axons are cut, their axons degenerate and the RGCs themselves subsequently die, presumably because they fail to get needed survival signals. In addition, we have recently found that electrical activity of RGCs, which may be diminished after injury, is necessary for their responsiveness to these factors. These findings raise a question, do RGC axons fail to regenerate after injury primarily because RGCs fail to survive? To test this hypothesis, we will first further characterize the signaling mechanisms that normally promote RGC survival. We have previously developed methods to purify and culture rat RGCs and found that the purified RGCs rapidly undergo programmed cell death in the absence of survival-promoting signals from their normal neighboring cell types. Several of these survival signals have already been elucidated and our preliminary results provide clear evidence for two new survival signals for RGCs produced by optic rectum and oligodendrocytes. We propose to further characterize and clone these signals. Secondly, we have found that electrically active RGCs are more responsive to their trophic factors and that this effect can be mimicked by increasing their intracellular levels of cAMP. We will investigate how electrical activity enhances the ability of RGCs to respond to their peptide trophic factors. Our ultimate goal is to determine whether in vivo delivery of RGC survival factors together with substances that mimic electrical activity will promote axonal regeneration after injury.

描述（作者）：我们建议研究为什么中央视觉 途径在受伤后无法再生以及如何修复 增强。我们将专注于通常控制的机制 视网膜神经节细胞（RGC）及其轴突的生存和生长， 以及成年少突胶质细胞前体细胞的特性， 受伤后可疑的新少突胶质细胞来源。大鼠光学元件 神经，主要由视网膜神经节细胞轴突和 髓鞘的寡聚细胞将用作模型系统。这 RGC及其轴突的存活通常由肽控制 信号，例如脑衍生的神经营养因子（BDNF），即 由邻近细胞（直肠靶神经元）释放 星形胶质细胞和少突胶质细胞 - 然后逆转到 细胞体。切割RGC轴突时，它们的轴突退化和RGC 自己随后死亡，大概是因为他们不需要 生存信号。此外，我们最近发现了电气 受伤后可能会减少RGC的活动是必要的 他们对这些因素的反应。这些发现提出了一个问题， RGC轴突是否在受伤后无法再生，主要是因为RGC失败了 生存？为了检验这一假设，我们将首先进一步表征 通常促进RGC存活的信号传导机制。我们有 以前开发了净化和培养大鼠RGC并发现的方法 纯化的RGC迅速在 从其正常邻近细胞中没有生存信号 类型。这些生存信号中的几个已经阐明 我们的初步结果为两个新生存提供了明确的证据 光直肠和少突胶质细胞产生的RGC的信号。我们 提议进一步表征和克隆这些信号。其次，我们 已经发现电活动的RGC对其 营养因素，可以通过增加它们的效果来模仿 细胞内cAMP。我们将研究如何电气 活动增强了RGC对其肽反应的能力 营养因素。我们的最终目标是确定体内是否 递送RGC生存因子以及模仿的物质 电活动将在受伤后促进轴突再生。