RETINAL GANGLION CELL PLASTICITY IN GLAUCOMA

青光眼是一种高患病率的疾病，其导致视网膜神经节细胞（RGC）的进行性损伤和死亡，从而导致失明。我们的长期目标是防止青光眼早期RGC死亡，并保留视功能。本研究的目的是i）表征OBA/2 J（02）青光眼小鼠模型以及具有遗传改变的细胞死亡途径的同类品系中的疾病史，和ii）确定急性IOP变化时RGC功能的可修饰性。我们的中心假设是RGC在死亡前经历了IOP依赖性的可逆功能障碍阶段，并且RGC功能障碍是由于对眼内压（IOP）的耐受性受损。我们的研究将包括具有自发性IOP升高和进行性RGC变性的02只小鼠;没有IOP升高和青光眼的独特同类品系;具有IOP升高但经遗传改变以增加RGC树突、RGC体或RGC轴突对应激的抗性的三种独特同类品系。我们的具体目标是，1）表征02菌株中疾病的自然结构·功能进展，2）表征02菌株中RGC功能对急性IOP损伤的可修饰性。我们将使用最先进的图形视网膜电图（PERG）、皮层视觉诱发电位（VEP）和光学相干断层扫描（OCT）分别作为RGC功能和RGC轴突数量的替代指标。PERG损失是由活性RGC活性降低和死亡RGC活性缺乏引起的。OCT损失是由于死亡的RGC缺乏轴突。我们还将使用一种新的、无创的方法，根据身体姿势的变化进行急性IOP升高/降低。本建议中使用的技术也可以转化为临床实践，并且所测试的假设也可能是临床青光眼的关键。中心假设得到了强有力的初步结果的支持，这些结果表明RGC功能障碍先于RGC死亡，并且RGC功能障碍可能因身体姿势变化获得的生理性IOP升高/降低而暂时加剧/改善。其基本原理是，这种创新的方法将提供一组生理标志物来检测RGC的易感性并预测其命运。这一结果将具有高度的意义，以确定个人在高风险的发展青光眼损害，并确定治疗的必要性。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方面的专家。

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.