RETINAL GANGLION CELL PLASTICITY IN GLAUCOMA

青光眼是一种高发疾病，可导致视网膜神经节细胞(RGC)进行性损害和死亡，导致失明。我们的长期目标是防止RGC在青光眼早期死亡，并保留视觉功能。本研究的目的是：1)研究OBA/2J(02)小鼠青光眼模型的病史，以及细胞死亡途径发生遗传改变的同源菌株的病史；2)确定急性LOP变化时RGC功能的可调性。我们的中心假设是RGC在死亡前经历了一段依赖眼压的可逆性功能障碍，RGC功能障碍是由于对眼压的耐受性(LOP)受损。我们的研究将包括02只患有自发性LOP升高和进行性RGC变性的小鼠；一个独特的没有LOP升高和青光眼的同源菌株；三个独特的LOP升高但经过基因改变的同源菌株，以增加RGC树突、RGC小体或RGC轴突对应激的抵抗力。我们的具体目标是，1)表征02株菌株疾病的自然结构和功能进展，2)表征02株菌株RGC功能对急性LOP损伤的可调性。我们将使用最先进的模式视网膜电信号(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的丧失既是由于存活的RGC活性降低，也是由于死亡的RGC缺乏活性。OCT损失是由于缺乏大量死亡的RGC造成的。我们还将使用一种新的、非侵入性的方法来根据体位的变化来进行急性LOP的升高/降低。这项建议中使用的技术也可以转化为临床实践，所测试的假设也可能在临床青光眼中起关键作用。这一中心假说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，随着体位的改变，生理性的LOP升高/降低可能会暂时加剧/改善RGC功能障碍。其基本原理是，这种创新的方法将提供一套生理标记物来检测视网膜节细胞的易感性并预测其命运。这一结果将对确定青光眼损害的高危人群和确定治疗的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.