Electron Microscopic Studies of Crystalline Lenses

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DESCRIPTION (provided by applicant): The long term objective of our research program is to elucidate the normal morphology in vertebrate lenses as it relates to human lens function. This information serves as the baseline for additional study of how age-related and/or pathological changes in lenses are manifested as compromised lens optical quality (decreased sharpness of focus and increased light scatter) leading ultimately to the development of specific cataracts. In the last three grant periods we have shown that on the basis of sutural anatomy, there are four different types of lenses. Variations in sutural complexity correlate with lens optical quality. Furthermore, we have shown how malformation of posterior sutures during development (autosomal recessive retinitis pigmentosa [ARRP]), as a consequence of some ocular surgery (vitrectomy), systemic disease (diabetes), and chronic treatment to mediate long-lasting neural and behavioral plasticity, all lead to posterior subcapsular cataract (PSC) formation. More importantly, we have found that at least some of these PSCs can be prevented or reversed with significant restoration of lens optical quality. The studies proposed in the next five years of this grant are designed to expand on our previous studies and accomplish the following specific aims: 1) to characterize the structure/function relationship of cataracts (PSCs typically formed in the short term [>50% of all patients) and nuclear sclerotic cataracts that arise in the long term (>50% of all older patients) as a complication of vitrectomy or trabeculectomy in an established animal model; 2) to characterize, for the first time, the relationship between lens sutures and dynamic focusing (accommodation and non-accommodation) in young vs. old avian (chicken), non-primate, mammalian (rabbit), primate (monkey and baboon)and human lenses; and 3) to continue to elucidate the contributions of the major fiber membrane proteins to lens function during development and growth in MIP, MP19, Cx46 and Cx50 knockout mice. In these studies we will utilize an improved preparative protocol for SDS-fracture labelling developed in our laboratory, that guarantees, for the first time, immunolabelling of the major membrane proteins along fiber length (on and off lens sutures) and throughout fiber development and growth. The results of all animal studies must be qualified when extrapolating to the human condition. However, if the factors that are responsible for PSC, nuclear sclerotic and congenital cataract formation in the above studies using animal models are similar to those that exist in the human condition, then a greater understanding of the relationship between lens structure and function afforded by techniques that we have developed and routinely apply in our laboratory, should lead to earlier detection and improved clinical management of cataracts in humans irrespective of their etiopathology.