Transparent cellular structure is the fundamental property of the biological lens. The next five year application will investigate the molecular basis for the transparent structure of lens cells. The PI's past studies of the collective interactions measured by Tc led to a clinical trial of pantethine as an anticataract agent in humans. Pantethine was used because it was effective against protein aggregation and lens opacification in animal models. During the next five years, the functional motifs of selected human lens proteins that appear to be involved with the interactions important for development and maintenance of lens cell transparency will be investigated. Recombinant human lens crystallins (wild-type and mutant) will be expressed, purified and characterized using biochemical assays for interactions involving human crystallins (AIM 1). Novel quantitative methods for Fourier, power law and fractal analysis will be used to characterize the microscopic structure of lens cells and of model solutions of human lens cytoplasmic proteins (AIM 2). The methods will be used to investigate and quantify the size and order/disorder of major structural components found in lens cytoplasm and will evaluate the fractal dimension of lens cell structure. Preliminary results suggest that alpha B crystallin and cytoskeletal proteins have important functions in the development and maintenance of lens cell transparency. Transgenic and knockout models for cataract will be used for in vivo studies of the relationships between lens crystallins, cytoskeletal proteins and lens opacification (AIM 3). The results of the proposed studies will have direct application in the design and testing of new therapeutic approaches to inhibit protein aggregation and lens opacification in humans.
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