Opacification of the eye lens, or cataract, is the leading cause of vision loss worldwide and represents the single major reason for ophthalmic surgery, particularly in those over fifty years of age. In this study, we aim to define the role of the gene for lens major intrinsic protein (MIP) in a hereditary form of cataract. MIP is the founder member of the water-channel family of transmembrane proteins, however, its role in lens biology is poorly understood. In our preliminary studies we have identified three strains of mice that inherit distinct mutations in the MIP gene. We will undertake a combined molecular and cell biological analysis of lenses from these mutant mice in order to define the underlying pathological mechanisms that lead to cataract development. Confocal microscopy image analysis and electron microscopy techniques will be used to determine the consequences of MIP mutations in fiber cell organization and suture formation along the optical axis of the lens. Electrophysiological techniques will be used to measure the effects of MIP mutations on lens water transport properties and osmotic sensitivity to cataract formation. Molecular and cell biology techniques will be used to identify the cytotoxic mechanisms by which MIP mutations cause fiber cell death and to determine if pharmacological agents can ameliorate agents can ameliorate or even prevent this sight threatening process. Ultimately, these studies will provide new insights regarding the role of MIP in lens development and provide a relevant model system for MIP-related cataract in humans.
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