REVERSIBLE GANGLION CELL DYSFUNCTION IN GLAUCOMA

青光眼可逆性神经节细胞功能障碍

• 批准号: 7995181
• 负责人: VITTORIO PORCIATTI
• 金额: $ 36.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995181
• 关键词: Address; Adverse effects; African American; American; Axon; Beds; Biological Markers; Biometry; Biophysics; Blindness; Cell Death; Cell physiology; Cessation of life; Clinical; Clinical Management; Cross-Sectional Studies; Data; Deterioration; Disease; Drops; Electrophysiology (science); Electroretinography; Ethnic Origin; Exposure to; Eye; Functional disorder; Funding; Future; Glaucoma; Goals; Hispanics; Homeostasis; Image; Individual; Letters; Longevity; Longitudinal Studies; Measurement; Measures; Metabolic; Metabolism; Modeling; Names; National Eye Institute; Natural History; Neuropathy; Ophthalmology; Optical Coherence Tomography; Outcome; Patients; Pattern; Photic Stimulation; Physiologic Intraocular Pressure; Population; Predisposition; Prevalence; Prevention; Principal Investigator; Quality of life; Recovery; Research; Retinal; Retinal Ganglion Cells; Risk; Severities; Staging; Stress; Structure; Structure-Activity Relationship; Suspect Glaucomas; Time; Vision research; Visual; alternative treatment; body position; carboxyl radical; cohort; cost effective; ganglion cell; high risk; improved; innovation; loss of function; older patient; pressure; prevent; programs; response; visual stimulus

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.

描述（由申请人提供）：青光眼会导致视网膜神经节细胞（RGC）进行性损伤和死亡，从而导致失明。预计到 2020 年，该疾病的患病人数将增至 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 在死亡前会经历一个可逆功能障碍阶段，而 RGC 功能障碍是由于眼压 (IOP) 耐受性受损所致。我们的研究将包括至少 500 名患有或发展青光眼风险较高的受试者和至少 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，从而扩展 2004 年启动的纵向研究，2) 表征 RGC 功能对 IOP 增加和代谢挑战的耐受性，3) 验证 RGC 功能障碍的测量结果作为生物标志物，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) 分别作为 RGC 功能和 RGC 轴突数量的非侵入性替代测量。 PERG 损失是由于活 RGC 活性降低和死 RGC 活性缺乏造成的。 OCT 损失是由于死亡 RGC 缺乏轴突造成的。我们之前的结果支持了中心假设，该结果表明，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 的治疗来改善。初步数据表明，PERG 缺陷可能是由于体位变化引起的眼压升高或长时间暴露于具有代谢挑战性的视觉刺激而暂时引起的。其基本原理是，这种创新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。这一结果对于识别发生青光眼损伤的高风险个体并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。我们的临床环境拥有大量独特的青光眼患者和老年受试者，由于非裔美国人和西班牙裔美国人，青光眼的风险增加。随着时间的推移，通过图形视网膜电图非侵入性测量的视网膜神经节细胞的电活动可能会在怀疑患有青光眼的受试者中发生改变，或者可能会因躺在床上导致眼压增加或因凝视对比图像而加速视网膜新陈代谢而产生的非侵入性压力而暂时改变。这些功能性生物标志物对于疾病的临床管理具有很大的相关性，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恶化。