GENE EXPRESSION IN AXOTOMIZED RETINAL GANGLION CELLS

轴切视网膜神经节细胞中的基因表达

• 批准号: 6195717
• 负责人: Leonard A Levin
• 金额: $ 28.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-04 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6195717
• 关键词: apoptosis; axon reaction; eye injury; free radical oxygen; gene expression; in situ hybridization; laboratory rat; molecular pathology; nerve injury; optic nerve; organ culture; retinal ganglion; transfection

DESCRIPTION: (Applicant's Abstract) Retinal ganglion cell (RGC) death is the final common pathway for glaucoma and virtually all other optic neuropathies. The initial insult in most optic nerve diseases is injury to the RGC axon, from either compression, ischemia, inflammation, or transection. Optic nerve injury results in RGC apoptosis, and this has been theorized to occur by interference with retrograde transport of target-derived neurotrophic factors or other mechanisms. Given that (1) axotomy induces RGC apoptosis and (2) most optic neuropathies are associated with initial axonal damage and subsequent RGC loss, RGC axotomy is an experimental model for understanding the pathophysiology of glaucomatous and other optic neuropathies. Our overall goal is to ascertain the molecular changes that occur within the RGC after axotomy, particularly those leading to induction of the apoptosis cascade, as well as hypothetical protective mechanisms. Our working hypothesis is that one of the critical molecular events underlying RGC death after axonal injury is generation of an intracellular reactive oxygen species (ROS) signal. Our long-term goal is to find ways of preventing RGC death from axonal injury by modulating these mechanisms. To test this hypothesis, we propose the following: (1) Determine whether generation of ROS is a necessary and sufficient step for initiation of a series of events leading to RGC apoptosis after axotomy; (2) Test whether endogenous regulation of ROS can act as a defense mechanism governing the RGC response to axotomy; (3) Test whether the mechanism by which ROS signal RGC death after axotomy involves opening of the mitochondrial permeability transition pore. Almost all optic neuropathies involve RGC axonal injury, except for a few disorders where the locus of injury is unknown. If ROS generation is essential for RGC death after axotomy, then this could serve as a critical point for therapeutic intervention. The health-relatedness of this proposal is that an understanding of the molecular response of the RGC to axonal injury would be applicable to a wide variety of diseases of the optic nerve, independent of the mechanism by which the nerve is injured. As many of these diseases (e.g., normal-tension glaucoma and ischemic optic neuropathy) are not easily treatable, determination of the regulation of cell destructive and protective mechanisms could lead to innovative new therapies.

描述：（申请人摘要） 视网膜神经节细胞（RGC）死亡是青光眼的最终共同途径， 几乎所有其他视神经病变。大多数视神经的初始损伤 疾病是RGC轴突的损伤，无论是压缩，缺血， 炎症或横切。视神经损伤导致RGC凋亡， 理论上这是通过干扰 靶源性神经营养因子或其他机制。 鉴于（1）轴突切断诱导RGC凋亡和（2）大多数视神经病变 与最初的轴突损伤和随后的RGC丢失，RGC轴突切断术相关 是一个实验模型，用于了解脑水肿的病理生理学， 和其他视神经病变。我们的总体目标是确定 轴突切断后RGC内发生的变化，特别是导致 诱导凋亡级联反应，以及假设的保护性 机制等我们的工作假设是关键的分子事件之一 轴突损伤后潜在的RGC死亡是细胞内 活性氧（ROS）信号。我们的长期目标是找到 通过调节这些机制防止RGC因轴突损伤而死亡。 为了检验这一假设，我们提出以下建议：（1）确定是否 ROS的产生是引发一系列 轴突切断后导致RGC凋亡的事件;（2）测试是否内源性 ROS的调节可以作为一种防御机制，控制RGC对 （3）检测ROS信号RGC死亡的机制是否与RGC死亡有关。 轴突切断术涉及线粒体通透性转换孔的开放。 几乎所有视神经病都涉及RGC轴突损伤，少数除外 损伤部位未知的疾病。如果ROS的产生是必不可少的 对于RGC在轴突切断后死亡，那么这可以作为一个临界点， 治疗干预这项建议的健康相关性是， 了解RGC对轴突损伤的分子反应将是 适用于各种各样的视神经疾病，独立于 神经损伤的机制。许多疾病（例如， 正常眼压性青光眼和缺血性视神经病变）不容易 可治疗的，确定细胞破坏性和保护性的调节 机制可能导致创新的新疗法。