Age related changes in lens transport and cataract

项目总结/摘要 白内障是世界范围内致盲的主要原因，人类白内障最常见的危险因素是 只是老化。世界卫生组织已经确定白内障是导致视力丧失的原因之一， 40岁以上的美国人，以及80岁以上的一半美国人。我们的假设是 老化对透镜运输、降解离子和水的体内平衡、以及产生 透镜含水量。这种随年龄增长的水传输下降改变了透镜的光学特性， 最初导致视力变化，最终表现为白内障，并最终需要手术 纠正一下为了确定潜在的新型抗白内障疗法，我们的策略将是研究 调节产生维持水含量的微循环系统的运输蛋白， 透镜的光学性质。未来确定的任何治疗干预措施的临床试验将需要 纵向监测体内人透镜的水传输状态和光学特性的方法。到 能够在健康志愿者受试者中进行临床评估，并允许早期的病理变化生物标志物， 水运输被检测，我们将开发磁共振成像方法，以非侵入性 跟踪人的透镜的光学特性。为了实现这些目标，我们将确定一些机制， 调节体外转运透镜的特定分子组分的活性。然后我们将确定 调节离体完整透镜中转运活性的药理学干预。我们还将使用 磁共振成像（MRI）在空间上映射改变透镜水运输对总自由 水含量、水与蛋白质的比率（折射率）和透镜表面几何形状， 缺乏转运的药理学修饰剂。最后，我们将开发新的MRI成像协议， 能够监测志愿者受试者中透镜纵向运输的关键参数。这些拟议 研究不仅有可能揭示延缓白内障发病的可能治疗途径， 以及未来测试这些策略功效所需的成像方法。

Project Summary/Abstract Cataract is the leading cause of blindness worldwide and the most common risk factor for human cataract is simply aging. The World Health Organization has identified cataract as a cause of vision loss in one of six Americans over the age of 40, and half of Americans older than 80. It is our hypothesis that the process of aging has negative effects on lens transport, degrading ion and water homeostasis, and producing changes in lens water content. This age-dependent decline in water transport alters the optical properties of the lens, initially causing changes in vision that ultimately manifest as cataract and eventually require surgical correction. To identify potentially novel anti-cataract therapies, our strategy will be to study the pathways that regulate the transport proteins that generate the micro-circulation system that maintains the water content and optical properties of the lens. The future clinical testing of any therapeutic interventions identified will require methods to longitudinally monitor the water transport status and optical properties of the human lens in vivo. To enable clinical assessment in healthy volunteer subjects and allow early biomarkers of pathological changes in water transport to be detected, we will develop Magnetic Resonance Imaging methodologies to non-invasively track the optical properties of the human lens. To achieve these goals, we will identify mechanisms that regulate activity of the specific molecular components of lens transport in vitro. We will then identify pharmacological interventions that regulate transport activity in the intact lens ex vivo. We will also use Magnetic Resonance Imaging (MRI) to spatially map the effect changing lens water transport has on total free water content, the water to protein ratio (refractive index) and lens surface geometry in the presence and absence of pharmacological modifiers of transport. Finally, we will develop new MRI imaging protocols to be able to monitor key parameters of lens transport longitudinally in volunteer human subjects. These proposed studies have the potential to not only reveal possible therapeutic pathways to delay the onset of cataract, but also the imaging methods required for future tests of the efficacy of these strategies.