Age related changes in lens transport and cataract

晶状体运输和白内障的年龄相关变化

• 批准号: 10475686
• 负责人: THOMAS W WHITE
• 金额: $ 33.68万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475686
• 关键词: Age; Aging; Biological; Biometry; Blindness; Carrier Proteins; Cataract; Cataract Extraction; Cell physiology; Ciliary Muscle; Clinical; Development; Elderly; Excision; Expenditure; Eye; Failure; Feedback; Financial Hardship; Funding; Future; Gap Junctions; Geometry; Healthcare; Homeostasis; Human; Human Volunteers; Hydrostatic Pressure; Image; Impairment; Ion Channel; Ion Transport; Ions; Knowledge; Lead; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Maintenance; Maps; Measurement; Measures; Mechanics; Mediating; Medicare; Microcirculation; Modeling; Monitor; Mus; Muscle relaxation phase; Nuclear; Nutrient; Operative Surgical Procedures; Optics; Oxygen; Pathology; Patients; Pharmacology; Presbyopia; Process; Property; Proteins; Protocols documentation; Refractive Errors; Refractive Indices; Scanning; Schedule; Shapes; Signal Pathway; Stimulus; Structure; Surface; System; Testing; Time; Transgenic Mice; Translating; Tropicamide; Visit; Vitrectomy; Water; Wild Type Mouse; World Health Organization; age related; base; cohort; cycloplegic; electric impedance; genetic manipulation; human subject; in vivo; insight; lens; middle age; mouse model; new therapeutic target; normal aging; novel therapeutic intervention; prevent; tool

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.

项目总结/摘要 透镜病理老视和白内障是年龄相关的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）和其固有的折射率梯度（水与蛋白质的比率），这反过来又 由内部微循环系统提供的细胞生理学维持。该系统利用 离子通道、转运蛋白和间隙连接的空间差异，以建立常设的电化学和 流体静压梯度以驱动离子、水和营养物通过无血管透镜的输送。它 我们假设老化过程对透镜运输、降解离子和水有负面影响 稳态，并产生透镜含水量的变化。随着年龄的增长， 改变了透镜的光学特性，导致光学质量和反射幅度的变化， 最初导致中年老视，最终表现为需要手术矫正白内障 在老年人中。为了验证这一假设，我们建议确定额外的组件调节水的运输 在离体完整小鼠透镜中的活性。我们将使用阻抗和细胞内静水压力 测量以监测具有药理学阻断或靶向的小鼠中的细胞内水转运 运输蛋白的缺失。然后，我们将使用磁共振成像（MRI）在空间上映射效果 改变小鼠透镜水转运对总游离水含量、水与蛋白质的比率（折射率）、晶状体水转运的影响 折射率）和透镜表面几何形状。研究透镜含水量的变化是否与 人类白内障的发病和进展，我们最近开发的基于MRI的体内光学模型 平台将应用于计划接受玻璃体切除术的患者和年龄匹配的对照 科目研究玻璃体切除术患者将允许白内障形成前水运输的变化， 与正常衰老的人类相比，在加速的时间框架内纵向跟踪。研究 为了研究在人体透镜内调节过程中透镜几何形状和水分布之间的关系，我们 将使用我们的MRI成像方案，以非侵入性方式监测志愿者透镜转运的关键参数 在住宿期间的人。这些拟议的研究将使用转基因小鼠模型， 机械的见解如何透镜水运输有助于维持的光学性质， 透镜，然后将其转化为人类研究，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。这些研究的见解可能会导致 涉及新的治疗干预以减轻年龄相关的透镜病理的负担。