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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由于视网膜神经节细胞死亡所致 (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。本项目研究的是在小鼠青光眼实验模型和小鼠青光眼实验模型中，青光眼患者死后的眼组织。它已经确定并将澄清第一个问题， RGC死亡的步骤，并将调查干预措施，防止RGC损失在第二个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）诱导的力直接和间接传递到RGC损伤中。一系列将对精心挑选的转基因小鼠品系进行研究，以确定眼睛对IOP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的神经元损伤。因为其中一半对于在正常IOP水平下遭受RGC损失的开角型青光眼，我们将确定候选者分子和相互作用在眼睛的支持组织，鼓励青光眼损害，眼压正常。其次，我们将确定在何种程度上改变毛细血管功能的光学神经头参与RGC损伤，可能由肿瘤坏死因子α介导，内皮素通常认为正常血管营养的失败在青光眼中起作用，但实际损坏的机制尚未详细说明。最后，我们将剖析cjun如何 N-末端激酶作为启动RGC死亡的初始信号参与。转基因小鼠缺乏这种分子将用于确定潜在的治疗效果，消除这个信号。该项目将综合目前关于早期青光眼的一些知识领域以获得潜在新疗法的连贯画面。遗传学候选分子青光眼易感性可能被鉴定。