Age related changes in lens transport and cataract

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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.