REVERSIBLE GANGLION CELL DYSFUNCTION IN GLAUCOMA

描述（由申请人提供）：青光眼导致视网膜神经节细胞（RGCs）的进行性损伤和死亡，导致失明。到2020年，这种疾病的流行率预计将上升到300万美国人。我们的长期目标是防止在青光眼的早期阶段发生研资局人员死亡。本研究的目的是确定功能失调的rgc及其恢复的机会窗口。我们的中心假设是RGC在死亡前经历了一个可逆性功能障碍阶段，RGC功能障碍是由于眼压耐受性受损。我们的研究将包括至少500名患有或发展青光眼风险增加的受试者和至少100名正常对照。我们的具体目标是：1)识别功能失调的RGC并评估其寿命，从而延长2004年开始的纵向研究；2)表征RGC功能对IOP升高和代谢挑战的耐受性；3)验证RGC功能失调的测量作为预测未来功能和结构损失严重程度的生物标志物。我们将分别使用视网膜电图（PERG）和光学相干断层扫描（OCT）作为RGC功能和RGC轴突数量的非侵入性替代测量。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的轴突缺失所致。我们之前的研究结果支持了中心假设，即早期青光眼的PERG缺陷相对大于OCT缺陷，并且可以通过降低眼压治疗来改善。初步数据显示，由于体位改变引起的IOP升高或长时间暴露于具有代谢挑战性的视觉刺激，可能会暂时引起PERG缺陷。其基本原理是，这种创新的方法将提供一套功能性生物标志物来检测rgc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青光眼、视电生理学、视网膜成像、生物物理学和生物统计学方面的专家。我们的临床环境有一个独特的大量青光眼患者和老年受试者，由于非裔美国人和西班牙裔种族，青光眼的风险增加。在怀疑患有青光眼的受试者中，视网膜神经节细胞的电活动可能会随着时间的推移而改变，或者在躺在床上增加眼压或盯着对比图像加速视网膜代谢时，可能会因非侵入性应激而暂时改变。这些功能性生物标志物与疾病的临床管理有很大的相关性，可以预测未来进展的严重程度，确定降压治疗的必要性，使预防成为一种具有成本效益的措施，并限制副作用的影响和生活质量的恶化。

DESCRIPTION (provided by applicant): Glaucoma causes progressive damage and death of retinal ganglion cells (RGCs) resulting in blindness. The prevalence of the disease will rise to a projected 3 million Americans by 2020. Our long-term goal is to prevent RGC death in the early stages of glaucoma. The objective of this study is to identify dysfunctioning RGCs and the window of opportunity for their recovery. Our central hypothesis is that RGCs undergo a stage of reversible dysfunction before dying, and that RGC dysfunction is due to impaired tolerance to intraocular pressure (IOP). Our study will include at least 500 subjects at increased risk of having or developing glaucoma and at least 100 normal controls. Our specific aims are 1) to identify dysfunctional RGCs and evaluate their lifespan, thereby extending the longitudinal study initiated in 2004, 2) to characterize the tolerance of RGC function to both IOP increase and metabolic challenge, and 3) to validate measurements of RGC dysfunction as biomarkers to predict severity of future functional and structural loss. We will use the Pattern Electroretinogram (PERG) and Optical Coherence Tomography (OCT) as non-invasive 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 of axons of dead RGCs. The central hypothesis is supported by our previous results showing that in early glaucoma PERG deficits are relatively larger than OCT deficits, and may be improved by IOP-lowering treatment. Preliminary data show that PERG deficits may be temporarily induced by either IOP elevation obtained with change in body position or by prolonged exposure to metabolically challenging visual stimuli. The rationale is that this innovative approach will provide a set of functional biomarkers to detect susceptibility of RGCs and predict their fate. This outcome will have high significance on identifying individuals at high-risk of developing glaucoma damage and determining the necessity of treatment. Our research team includes experts in glaucoma, visual electrophysiology, retinal imaging, biophysics, and biostatistics. Our clinical setting has a uniquely large population of glaucoma patients and older subjects at increased risk of glaucoma due to African-American and Hispanic ethnicity. The electrical activity of retinal ganglion cells non-invasively measured by pattern electroretinogram over time may be altered in subjects suspected of having glaucoma, or may become temporarily altered in response to a non-invasive stress occurring when the eye pressure is increased by lying on a bed, or the retinal metabolism is accelerated by staring at a contrasted image. These functional biomarkers have great relevance for clinical management of the disease in order to predict future severity of progression, determine the necessity of pressure-lowering treatment, make prevention a cost-effective measure, and limit the impact of side effects and deterioration of quality of life.