RETINAL GANGLION CELL PLASTICITY IN GLAUCOMA

青光眼视网膜神经节细胞的可塑性

• 批准号: 7895585
• 负责人: VITTORIO PORCIATTI
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895585
• 关键词: Acute; Address; Age; Age-Months; Apoptosis; Apoptotic; Arts; Axon; Biological Markers; Biometry; Biophysics; Blindness; Cell Death; Cell physiology; Cessation of life; Chronic; Clinical; Congenic Strain; Dendrites; Dependence; Disease; Disease Outcome; Disease Progression; Electrophysiology (science); Electroretinography; Evoked Potentials; Eye; Figs - dietary; Functional disorder; Funding; Future; Genetic Predisposition to Disease; Glaucoma; Goals; Head; High Prevalence; Image; Individual; Laboratories; Life Expectancy; Measures; Methods; Modeling; Mouse Strains; Mus; Mutation; National Eye Institute; Neurons; Neuropathy; Noise; Optic Nerve; Optical Coherence Tomography; Outcome; Pathway interactions; Pattern; Physiologic Intraocular Pressure; Physiological; Posture; Predisposition; Process; Recording of previous events; Research; Research Priority; Residual state; Resistance; Retinal; Retinal Ganglion Cells; Signal Transduction; Staging; Stress; Support System; Techniques; Testing; Thick; Time; Timolol Maleate; Translating; Vision; Visual; Work; base; clinical practice; congenic; design; disease natural history; glycoprotein NMB; high risk; improved; indexing; innovation; loss of function; mouse model; neuronal cell body; non-invasive monitor; novel; prevent; relating to nervous system; research study; resilience; retinal nerve fiber layer

Glaucoma is a disease with high prevalence that causes progressive damage and death of retinal ganglion cells (RGCs) resulting in blindness. Our long·term goal is to prevent RGC death in the early stages of glaucoma and spare visual function. The objectives of this study are i) to characterize the history of disease in the OBA/2J (02) mouse model of glaucoma as well as in congenic strains with genetically altered pathways of cell death and ii) to determine the modifiability of RGC function upon acute lOP changes. Our central hypothesis is that RGCs undergo a stage of IOP·dependent, reversible dysfunction before dying, and that RGC dysfunction is due to impaired tolerance to intraocular pressure (lOP). Our study will include 02 mice with spontaneous lOP elevation and progressive RGC degeneration; a unique congenic strain without lOP elevation and glaucoma; three unique congenic strains with lOP elevation but genetically altered to increase resistance of either RGC dendrites, RGC bodies or RGC axons to stress. Our specific aims are, 1) Characterize the natural structural·functional progression of disease in 02 strains, 2) Characterize the modifiability of RGC function to acute lOP insult in 02 strains. We will use state·of·the·art Pattern Electroretinogram (PERG), Cortical Visually Evoked Potentials (VEP) and Optical Coherence Tomography (OCT) as surrogate measures of RGC function and RGC axon number, respectively. PERG losses result from both reduced activity of viable RGCs and lack of activity of dead RGCs. OCT losses result from lack ofaxons of dead RGCs. We will also use a novel, non invasive method for acute lOP elevation/lowering based on changes of body posture. The techniques used in this proposal can also be translated into clinical practice, and the hypotheses tested may also be pivotal in clinical glaucoma. The central hypothesis is supported by strong preliminary results showing that RGC dysfunction precedes RGC death, and that RGC dysfunction may be temporarily exacerbated/improved by physiological lOP elevation/lowering obtained with changes in body posture. The rationale is that this innovative approach will provide a set of physiological markers to detect susceptibility of RGCs and predict their fate. This outcome will have high significance for identifying individuals at high-risk of developing glaucoma damage and determining the necessity of treatment. Our research team includes experts in experimental glaucoma, visual electrophysiology, retinal imaging, biophysics, and biostatistics.

青光眼是一种高患病率的疾病，会导致残留神经节细胞（RGC）的逐渐损害和死亡，导致失明。我们的长期目标是防止在青光眼和备用视觉功能的早期阶段RGC死亡。这项研究的目的是i）表征oba/2j（02）小鼠小鼠模型以及具有遗传改变的细胞死亡途径和ii）的疾病史，以确定RGC功能在急性LOP变化时功能的可修改性。我们的中心假设是，RGC在垂死前经历了IOP依赖性，可逆功能障碍的阶段，并且RGC功能障碍是由于对眼内压（LOP）的耐受性受损。我们的研究将包括02只小鼠，具有赞助的LOP升高和进行性RGC变性；独特的先天菌株，没有LOP升高和青光眼；三种独特的先天性菌株具有LOP升高，但在基因上改变了，以增加RGC树突，RGC体或RGC轴突的耐药性。我们的具体目的是，1）表征02菌株中疾病的自然结构功能进展，2）将RGC功能的可修改性表征为02菌株中的急性LOP损伤。我们将分别使用TART模式电图（PERG），皮质视觉诱发电位（VEP）和光学相干断层扫描（OCT）作为RGC功能和RGC轴突编号的替代测量。 PERG损失均由降低可行的RGC的活性和死亡RGC的活性。十月损失是由于缺乏死亡RGC的轴突而导致的。我们还将根据身体姿势的变化使用一种新型的非侵入性方法来急性LOP升高/降低。该提案中使用的技术也可以转化为临床实践，所测试的假设在临床青光眼中也可能是关键的。中心假设得到了强烈的初步结果的支持，表明RGC功能障碍先于RGC死亡，并且RGC功能障碍可能会暂时加重/改善，而随着身体姿势变化而获得的物理LOP升高/降低。理由是，这种创新的方法将提供一组生理标记，以检测RGC的敏感性并预测其命运。这种结果对于鉴定高风险的患者发展青光眼损害并确定必要的治疗将具有很高的意义。我们的研究团队包括实验性青光眼，视觉电生理学，视网膜成像，生物物理学和生物统计学专家。