GENE EXPRESSION IN AXOTOMIZED RETINAL GANGLION CELLS

描述：(申请人摘要) 视网膜神经节细胞(RGC)死亡是青光眼和青光眼的最终共同途径 几乎所有其他视神经疾病。最初对大多数视神经的侮辱 疾病是RGC轴突的损伤，要么是受压，要么是缺血， 炎症，或横切。视神经损伤导致RGC细胞凋亡， 这已经被理论上认为是由于干扰了逆行运输 靶向衍生神经营养因子或其他机制。 考虑到(1)轴突切断诱导RGC细胞凋亡和(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轴突切断有关 是了解青光眼病理生理学的实验模型。 以及其他视神经疾病。我们的总体目标是确定分子 轴突切断后在研资局内发生的变化，特别是导致 诱导细胞凋亡级联反应以及假说的保护作用 机械装置。我们的工作假设是，关键的分子事件之一 轴突损伤后RGC死亡的潜在原因是细胞内产生 活性氧(ROS)信号。我们的长期目标是找到 通过调节这些机制来预防RGC因轴突损伤而死亡。 为了验证这一假设，我们提出了以下建议：(1)确定是否 ROS的产生是启动一系列活动的必要且充分的步骤 轴突切断后导致RGC细胞凋亡的事件；(2)检测内源性 ROS的调节可以作为一种防御机制，管理RGC对 (3)检测ROS信号转导RGC死亡的机制 轴突切开术涉及打开线粒体通透性转换孔。 几乎所有的视神经病变都与RGC轴突损伤有关，除了少数 损伤部位不明的疾病。如果ROS生成是必不可少的 对于RGC在轴突切断后的死亡，这可能是一个临界点 治疗性干预。这项建议与健康有关的地方是 对RGC对轴突损伤的分子反应的理解将是 适用于多种视神经疾病，不依赖于 神经受损的机制。这些疾病中的许多(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，细胞破坏性和保护性调节的测定 这种机制可能会带来创新的新疗法。

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.