Pathogenesis of Glaucomatous Optic Nerve Damage

青光眼视神经损伤的发病机制

基本信息

批准号：
7646697
负责人：
Harry Alan Quigley
金额：
$ 36.91万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7646697
关键词：
Acute Affect Anatomy Area Axon Biomechanics Blindness Blood - brain barrier anatomy Blood Vessels Blood capillaries Cell Death Cessation of life Choroid Chronic Connective Tissue Elevation Endothelin Environment Equilibrium Experimental Models Eye Failure Gene Expression Genes Genetic Predisposition to Disease Glaucoma Head Human Indium Injury Intervention Knowledge Lead Life MAPK10 gene Measures Mediating Modeling Morphology Mouse Strains Mus Nerve Neuronal Injury Nutritional Support Open-Angle Glaucoma Optic Disk Optic Nerve Pathogenesis Permeability Persons Phosphotransferases Physiologic Intraocular Pressure Physiological Play Process Property Proteins Retina Retinal Ganglion Cells Role Sclera Series Signal Transduction Stress Therapeutic Tissues Transgenic Mice Transgenic Organisms Translations Tumor Necrosis Factor-alpha Tumor Necrosis Factors capillary cell injury cytokine extracellular human TNF protein neuronal cell body nutrition prevent response stress-activated protein kinase 1 transcription factor

项目摘要

The loss of vision caused by glaucoma results from death of retinal ganglion cells (RGC), whose intraretinal environment consists of interacting processes, some of which promote survival and others that lead toward death. This project studies initial alterations in the balance between life and death of RGC in both experimental models of glaucoma in mice and in the post-mortem ocular tissue of persons with glaucoma. It has identified and will clarify the first steps in RGC death, and will investigate interventions that prevent RGC loss in the second leading cause of worldwide blindness. First, we determine the role of specific connective tissue elements in the sclera that transmit intraocular pressure (IOP)-induced force directly and indirectly into RGC injury. A series of carefully chosen transgenic mouse strains will be studied to identify what alterations in the biomechanical response of the eye to IOP are most likely to either increase or decrease neuronal injury as measured in acute and chronic mouse glaucoma models. Since half of those with open-angle glaucoma suffer RGC loss at normal IOP levels, we will determine candidate molecules and interactions in the eye¿s support tissues that encourage glaucoma damage at normal IOP. Second, we will determine the extent to which altered capillary function at the optic nerve head contributes to RGC damage, perhaps mediated by tumor necrosis factor alpha and endothelin. Failure of normal vascular nutrition is generally agreed to play a role in glaucoma, but the mechanism(s) of actual damage have not been detailed. Finally, we will dissect how cjun n-terminal kinase participates as an initial signal to start RGC death. Transgenic mice deficient in this molecule will be used to determine the potential therapeutic benefit of eliminating this signal. The project will synthesize some areas of present knowledge about early glaucoma injury to derive a cohesive picture for potential new therapy. Candidate molecules for genetic susceptibility to glaucoma are likely to be identified.

青光眼引起的视力丧失是视网膜神经节细胞死亡的结果（RGC），其视网膜内环境由相互作用的过程组成，其中一些促进生存和其他导致死亡的因素该项目研究了最初的变化。小鼠和青光眼实验模型中 RGC 生与死的平衡青光眼患者的死后眼组织已经确定并将澄清第一个。 RGC 死亡的步骤，并将研究预防 RGC 损失的干预措施导致全球失明的主要原因。首先，我们确定巩膜中特定结缔组织成分的作用将眼内压 (IOP) 引起的力直接或间接传递至 RGC 损伤 A 系列。将研究精心挑选的转基因小鼠品系，以确定哪些变化眼睛对眼压的生物力学反应最有可能增加或减少在急性和慢性小鼠青光眼模型中测量到的神经元损伤。开角型青光眼在正常 IOP 水平下遭受 RGC 损失，我们将确定候选者眼睛中的分子和相互作用¿ s 支持组织，促进青光眼损伤其次，我们将确定光学器件毛细血管功能改变的程度。神经头导致 RGC 损伤，可能是由肿瘤坏死因子 α 和人们普遍认为，正常血管营养的失败在青光眼中发挥着作用。但实际造成伤害的机制还没有详细说明，最后我们来剖析一下cjun是如何造成的。 N 末端激酶作为启动 RGC 死亡的初始信号参与。该分子的缺陷将用于确定潜在的治疗益处消除该信号。该项目将综合有关早期青光眼的一些现有知识损伤以获得潜在新疗法候选分子的整体图景。可能会确定对青光眼的易感性。