The long-term objectives are (a) to elucidate specific structural features of the individual crystallins in the lens and the interactions between them that give rise to a transparent structure in normal lenses, and (b) to understand the cause and mechanism by which lenses become opaque upon cataract formation. In this project period, studies will focus on defining the factors responsible for protein-protein aggregation, protein modifications, and increased stability in the supramolecular organization in normal lens, and the mechanism of destabilization of protein structure during cataractogenesis.
The specific aims are: (1) To determine the mechanism of protein-protein interaction leading to aggregation and insolubilization in normal aging and cataractogenesis. Studies include structure and stability of individual crystallins isolated from bovine and human lens. (2) To define the factors responsible for protein modification, such as pigmentation, insolubilization, and aggregation in human lens. Intact human lens, young, aged, and cataractous, will be investigated to understand the mechanism of protein modifications. In addition, lenses from India and the US will be studied, as described above, to distinguish the protein modifications under different environmental conditions (such as light), food habits, and malnutrition. (3) To investigate the structural changes of lens proteins due to glycation, carbamylation, and Ca2+ ion. In addition to appropriate chemical, biochemical, and spectroscopic techniques such as absorption, fluorescence, and circular dichroism (CD), the project will also use high-resolution nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and nuclear magnetic relaxation dispersion (NMRD) techniques to accomplish the aims.
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