RETINAL GANGLION CELL PLASTICITY IN GLAUCOMA

青光眼是一种高患病率的疾病，可导致视网膜神经节细胞（RGCs）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早期青光眼患者死亡，并保护视力。本研究的目的是：(1)描述OBA/2J（02）型青光眼小鼠模型以及细胞死亡基因改变的同源菌株的病史；(2)确定急性lOP改变时RGC功能的可变性。我们的中心假设是，RGC在死亡前会经历一个IOP依赖性、可逆性功能障碍阶段，RGC功能障碍是由于眼压耐受性受损。我们的研究将包括02只自发性lOP升高和进行性RGC变性的小鼠；一个独特的同源菌株，没有lOP升高和青光眼；三种独特的同源菌株，lOP升高，但基因改变，以增加RGC树突，RGC体或RGC轴突对应激的抵抗力。我们的具体目标是，1)表征02菌株疾病的自然结构和功能进展，2)表征02菌株急性lOP损伤时RGC功能的可改变性。我们将分别使用视网膜电图（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轴突数量的替代测量方法。PERG损失是由于存活的rgc活性降低和死亡的rgc缺乏活性造成的。OCT损失是由于死亡rgc缺乏轴突造成的。我们还将使用一种新颖的、无创的方法来根据身体姿势的变化进行急性lOP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对临床青光眼至关重要。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功能障碍可能会因身体姿势的改变而暂时加剧/改善生理上的lOP升高/降低。其基本原理是，这种创新的方法将提供一套生理标记来检测RGCs的易感性并预测它们的命运。这一结果对于鉴别青光眼损伤高危人群和确定治疗必要性具有重要意义。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.