This project, directed toward elucidation of the molecular mechanisms responsible for cataratogensis, places special emphasis on the role of the structure and function of the lens crystallins. Until recently, the crystallins were thought to be simply structural elements of the lens protein matrix, without any specific quantifiable biological function. Two recent discoveries have provided new insights and approached to the physiological roles of the crystallin: (1) the crystallins either are functionally active enzymes or are at least related to proteins with specific biological activities and (2) alpha-crystallin is a molecular chaperon that can prevent the aggregation of denaturing proteins. Our group is studying the chaperon function of alpha-crystallin, with the goal of establishing its significance in the intact lens. Using the isolated crystallin, we have shown that it forms stable complexes with target proteins, specifically interacting with denaturing proteins at the earliest stage of denaturation. The specificity of this interaction has been demonstrated by the fact that in some instances it is strongly dependent on the availability of obligate cofactors of the target proteins. Studies on """"""""enzyme/crystallins"""""""" focus zelu-crystallin, a major protein in the lenses of certain mammals (eg, guinea pigs, camelids). In guinea pigs a mutation affects the lenticular function(s) of the protein, leading to cataract. The zelu-crystallin system also is being used to investigate the mechanisms of lens-specific expression of crystallin genes. Lens organ culture is being used as both a means of testing potential anticateract agents and a system for analyzing the responses of intact lenses to various cataractogenic stresses. The changes in gene expression induced in primate lenses by stress are being studied to identify specific proteins and processes important in combating stress. This information will facilitate more rational design of strategies to accomplish our ultimate goal: the prevention or delay of cataractogenesis.
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