GENE EXPRESSION IN AXOTOMIZED RETINAL GANGLION CELLS

轴切视网膜神经节细胞中的基因表达

基本信息

批准号：
6950900
负责人：
Leonard A Levin
金额：
$ 7.39万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-04 至 2005-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6950900
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

项目摘要

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：（申请人的摘要）视网膜神经节细胞（RGC）死亡是青光眼和几乎所有其他视力神经病。大多数视神经的最初侮辱疾病是对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，并理论上将其通过干扰逆行运输而发生目标衍生的神经营养因素或其他机制。鉴于（1）轴切开术会诱导RGC凋亡，（2）大多数视神经病变与初始轴突损伤和随后的RGC损失有关，RGC轴切开术是一种实验模型，用于了解青光眼的病理生理学和其他视神经病变。我们的总体目标是确定分子轴切开术后RGC内发生的变化，尤其是导致的变化诱导凋亡级联以及假设的保护性机制。我们的工作假设是关键分子事件之一轴突损伤后的基础RGC死亡是细胞内产生的活性氧（ROS）信号。我们的长期目标是找到通过调节这些机制来防止轴突损伤的RGC死亡。为了检验这一假设，我们提出以下建议：（1）确定是否是否 ROS的产生是启动系列的必要和足够的步骤导致轴切开术后RGC凋亡的事件；（2）测试是否内源性 ROS的调节可以充当控制RGC响应的防御机制轴切开术；（3）测试ROS Signal RGC死亡之后的机制是否轴切开术涉及打开线粒体通透性过渡孔。几乎所有的视神经病变都涉及RGC轴突损伤，除了一些伤害轨迹未知的疾病。如果ROS的产生是必不可少的对于轴突切开术后的RGC死亡，这可能是治疗干预。该提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视神经的多种疾病，独立于神经受伤的机制。这些疾病中的许多（例如正常张力青光眼和缺血性视神经病变不易可以治疗，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。