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Mitochondrial Dysfunction in Glaucomatous Optic Neuropathy

青光眼视神经病变中的线粒体功能障碍

基本信息

批准号：
9464735
负责人：
WONKYU JU
金额：
$ 3.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9464735
关键词：
Affect Axon Bioenergetics Biological Biological Preservation Blindness Cell Culture System Cell Death Cell Survival Cells Crista ampullaris Defect Dominant-Negative Mutation Down-Regulation Dynamin Electron Microscope Face Functional disorder Gene Expression Generations Genes Genus Hippocampus Glaucoma Goals Image Impairment In Vitro Link Mediating Mitochondria Mitochondrial DNA Molecular Morphology Mus NOS2A gene Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Optic Atrophy Optic Disk Optic tract structure Patients Physiologic Intraocular Pressure Primary Open Angle Glaucoma Production Progress Reports Proteins Reactive Oxygen Species Reporting Respiration Retina Retinal Ganglion Cells SKIL gene Scanning Structure Synapses Techniques Testing Vision Visual Pathways base in vivo in vivo imaging knock-down mitochondrial dysfunction mouse model mutant neuron loss nitrosative stress novel novel therapeutic intervention optic nerve disorder overexpression pressure protective effect public health relevance superior colliculus Corpora quadrigemina therapeutic target tomography

项目摘要

DESCRIPTION (provided by applicant): Glaucoma is the leading cause of irreversible blindness and affects more than 66 million people worldwide. The observations of abnormal mitochondrial respiration and down-regulation of mitochondrial fusion-related optic atrophy 1 (OPA1) gene expression in patients with primary open angle glaucoma suggest that mitochondrial dysfunction is as an important pathophysiological mechanism, contributing to glaucoma progression. We have identified that elevated intraocular pressure (IOP) triggers excessive mitochondrial fission and cristae depletion, as well as OPA1 gene deficiency in the retina and optic nerve head (ONH) of glaucomatous DBA/2J (D2) mice. Conversely, increased OPA1 expression promotes retinal ganglion cell (RGC) survival in D2 mice. Our preliminary results indicate elevated IOP impairs mitochondrial bioenergetics by reducing cellular ATP production and by increasing reactive oxygen species generation, as well as triggers formation of S-nitrosylation of the fission-promoting protein dynamin-related protein 1 (DRP1). More importantly, inhibition of DRP1 function by overexpression of dominant-negative DRP1 K38A mutant promotes RGC survival as well as preserves mitochondrial integrity in the ONH axons of glaucomatous D2 mice. The overall goal of this competitive renewal is to further characterize the pathophysiological consequences of altered mitochondrial dynamics (fission/fusion) and to assess their significance as therapeutic targets for protecting RGCs and its axons, as well as preserving structural integrity and synapses linking RGCs and the central visual pathway, and visual function in glaucoma. There are three specific aims: 1) To characterize the pathophysiological consequences of OPA1 deficiency or S-nitrosylation of DRP1 formation in RGCs. 2) To determine the protective effect of increasing OPA1 expression or inhibiting DRP1 function to ameliorate compromised mitochondrial integrity and bioenergetics in RGCs. 3) To determine whether increasing OPA1 expression or inhibiting DRP1 function can preserve the structural integrity and synapses linking RGCs and the central visual pathway, and visual function. This proposal will enhance our understanding of the pathophysiological mechanisms of mitochondrial dysfunction in glaucomatous neurodegeneration, and offer the scientific basis for identifying and developing new therapeutic strategies that could protect not only RGCs and their axons, but also the central visual pathway against glaucomatous damage.

描述（由申请人提供）：青光眼是不可逆性失明的主要原因，影响全球超过6600万人。在原发性开角型青光眼患者中观察到的异常线粒体呼吸和线粒体融合相关视神经萎缩1（OPA 1）基因表达的下调表明线粒体功能障碍是青光眼进展的重要病理生理机制。我们已经确定，眼内压（IOP）升高触发过度线粒体分裂和嵴耗竭，以及OPA 1基因缺陷的视网膜和视神经乳头（ONH）的青光眼DBA/2 J（D2）小鼠。相反，OPA 1表达增加促进D2小鼠视网膜神经节细胞（RGC）的存活。我们的初步结果表明，IOP升高通过减少细胞ATP产生和增加活性氧产生来损害线粒体生物能量学，并触发促分裂蛋白动力蛋白相关蛋白1（DRP 1）的S-亚硝基化形成。更重要的是，通过显性负性DRP 1 K38 A突变体的过表达抑制DRP 1功能促进RGC存活，并保留了D2小鼠ONH轴突中线粒体的完整性。这种竞争性更新的总体目标是进一步表征改变的线粒体动力学（分裂/融合）的病理生理学后果，并评估其作为保护RGC及其轴突的治疗靶点的意义，以及保留连接RGC和中央视觉通路的结构完整性和突触，以及青光眼中的视觉功能。本研究有三个具体的目的：1）描述OPA 1缺乏或RGC中DRP 1形成的S-亚硝基化的病理生理后果。2)确定增加OPA 1表达或抑制DRP 1功能对改善RGC中受损的线粒体完整性和生物能量学的保护作用。3)研究增加OPA 1表达或抑制DRP 1功能是否可以保护RGCs与中枢视觉通路的结构完整性和突触，以及视觉功能。这一发现将加深我们对青光眼性神经退行性变中线粒体功能障碍的病理生理机制的理解，并为识别和开发新的治疗策略提供科学依据，这些策略不仅可以保护RGCs及其轴突，而且还可以保护中枢视觉通路免受青光眼损害。