REVERSIBLE GANGLION CELL DYSFUNCTION IN GLAUCOMA

描述（由申请人提供）：青光眼引起视网膜神经节细胞（RGC）的进行性损伤和死亡，导致失明。到2020年，这种疾病的患病率预计将上升到300万美国人。我们的长期目标是预防青光眼早期阶段的RGC死亡。本研究的目的是确定功能障碍的RGC和他们的恢复的机会窗口。我们的中心假设是RGC在死亡前经历了一个可逆的功能障碍阶段，RGC功能障碍是由于对眼内压（IOP）的耐受性受损。我们的研究将包括至少500名患有或发展为青光眼的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）识别功能障碍的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功能障碍的测量值作为生物标志物，以预测未来功能和结构损失的严重程度。我们将使用图形视网膜电图（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措施，分别。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。我们先前的结果支持中心假设，表明在早期青光眼中，PERG缺陷相对大于OCT缺陷，并且可以通过降低IOP治疗来改善。初步数据表明，PERG缺陷可能是暂时诱导的IOP升高与身体位置的变化，或通过长期暴露于代谢挑战性的视觉刺激。其基本原理是，这种创新的方法将提供一组功能性生物标志物来检测RGC的易感性并预测其命运。这一结果对于识别青光眼损害的高危个体和确定治疗的必要性具有重要意义。我们的研究团队包括青光眼、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。我们的临床环境中有一个独特的大量青光眼患者和老年受试者的青光眼风险增加，由于非洲裔美国人和西班牙裔。通过模式视网膜电图随时间非侵入性测量的视网膜神经节细胞的电活动在怀疑患有青光眼的受试者中可能会改变，或者可能响应于当躺在床上使眼压增加时发生的非侵入性应激而暂时改变，或者通过凝视对比图像加速视网膜代谢。这些功能性生物标志物与疾病的临床管理具有很大的相关性，以便预测未来进展的严重程度，确定降压治疗的必要性，使预防成为具有成本效益的措施，并限制副作用和生活质量恶化的影响。

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.