Age related changes in lens transport and cataract

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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.