Age related changes in lens transport and cataract

项目摘要/摘要 晶状体病变老花眼和白内障是年龄相关性屈光不正和视力的主要原因。 当今世界的损失。透镜的透明度和折射特性由其几何形状决定 (形状和体积)及其固有的折射率梯度(水与蛋白质的比率)，它们依次是 由内部微循环系统提供的细胞生理维持。该系统利用 离子通道、转运体和缝隙连接的空间差异，以建立稳定的电化学和 静水压力梯度，以推动离子、水和营养物质通过无血管晶状体的运输。它 我们的假设是，老化过程对晶状体运输、降解离子和水分有负面影响吗？ 动态平衡，并产生晶状体水分含量的变化。这种与年龄相关的水运下降 改变晶状体的光学特性，导致光学质量和调节幅度的变化 最初导致中年老花眼，最终表现为需要手术矫正的白内障 在老年人身上。为了验证这一假设，我们建议确定调节水运输的其他成分。 在体外完整的小鼠晶状体中的活性。我们将使用阻抗和细胞内静水压力 药物阻断或靶向作用下监测小鼠细胞内水转运的方法 运输蛋白的缺失。然后我们将使用磁共振成像(MRI)在空间上绘制效果图 改变小鼠晶状体水转运对总自由水含量、水蛋白比(屈光度)的影响 折射率)和透镜表面几何形状。研究晶状体水分含量的变化是否与 人类白内障的发生和发展，我们最近开发的基于活体MRI的光学模型 平台将应用于计划接受玻璃体切除手术的患者和年龄匹配的对照组 研究对象。对玻璃体切除患者的研究将使白内障形成前水运输的变化成为可能 与正常衰老的人类相比，纵向跟踪的时间框架更快。为了研究 在活体人类晶状体调节过程中晶状体几何形状与水分分布的关系 将使用我们的MRI成像协议来无创性地监测志愿者晶状体传输的关键参数 住宿期间的人体受试者。这些拟议的研究将使用转基因小鼠模型来获得 关于透镜水运输如何有助于维持晶体的光学性质的机械论见解 透镜，然后将被转化为人体研究，以评估水运输如何有助于 老花眼的发展和核性白内障的发病。来自这些研究的见解可能会导致 提出新的治疗措施，以减轻年龄相关晶状体病变的负担。

Project Summary/Abstract The lens pathologies presbyopia and cataract are the leading causes of age related refractive error and vision loss in the world today. The transparency and refractive properties of the lens are determined by its geometry (shape and volume) and its inherent gradient of refractive index (water to protein ratio), which are in turn maintained by the cellular physiology provided by the internal microcirculation system. This system utilizes spatial differences in ion channels, transporters and gap junctions to establish standing electrochemical and hydrostatic pressure gradients to drive the transport of ions, water and nutrients through the avascular lens. 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, causing changes in optical quality and accommodative amplitude that initially result in presbyopia in middle age and ultimately manifest as cataract that requires surgical correction in the elderly. To test this hypothesis, we propose to identify additional components regulating water transport activity in the intact mouse lens ex vivo. We will use impedance and intracellular hydrostatic pressure measurements to monitor intracellular water transport in mice with pharmacological blockade or targeted deletions of transport proteins. We will then use Magnetic Resonance Imaging (MRI) to spatially map the effect changing mouse lens water transport has on total free water content, the water to protein ratio (refractive index) and lens surface geometry. To investigate whether changes in lens water content are associated with the onset and progression of human cataract, our recently developed in vivo MRI-based optical modelling platform will be applied to patients who are scheduled to undergo vitrectomy and age matched control subjects. Studying vitrectomy patients will allow changes in water transport preceding cataract formation to be followed longitudinally in an accelerated time frame compared to normally ageing humans. To study the relationship between lens geometry and water distribution during accommodation in the human lens in vivo, we will use our MRI imaging protocols to monitor key parameters of lens transport non-invasively in volunteer human subjects during accommodation. These proposed studies will use transgenic mouse models to gain mechanistic insights into how lens water transport contributes to maintenance of the optical properties of the lens, which will then be translated into human studies to assess how water transport contributes to the development of presbyopia and the onset of nuclear cataract. Insights from these studies could potentially lead to novel therapeutic interventions to alleviate the burden of the age-related lens pathologies.