ALPHA-CRYSTALLIN FUNCTION IN LENS BIOLOGY

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Project Summary Cataract formation is the most common cause of vision loss, accounting for 45% of blindness worldwide. Cataract operations cost the US Medicare system ~$5 billion annually. Epidemiological studies show that the pathogenesis of human cataracts involves genetic, environmental, and other disease-associated risk factors. Lens crystallins account for 90% of the total lens proteins and play a key role in lens transparency. Hereditary cataracts account for a significant proportion of childhood blindness, and 50% of these cataracts have a genetic basis. Much recent progress has been made in identifying point mutations in genes that encode ¿, ¿ and ¿-crystallins and lead to hereditary human cataracts at birth or an early age. Functional studies on these monogenic forms of cataract could provide important information about the etiology of age-related cataracts. ¿-crystallin is an aggregate of two polypeptides ¿A and ¿B which are expressed in lens epithelial and fiber cells. To understand disease etiology in hereditary cataracts, we have generated knock-in mouse models expressing the ¿- crystallin mutations ¿A-R49C and ¿B-R120G linked with human autosomal dominant hereditary cataracts, using embryonic stem cell-based technologies. These mice develop cataracts at an early stage and will be an important tool to understand disease process. Specific Aim 1 will test the hypothesis that the ¿A-crystallin mutant causes epithelial and fiber cell disruption soon after the mutant protein is expressed in the developing lens. The second Specific Aim tests the hypothesis that the interaction between mutant ¿-crystallin, cytoskeletal proteins and adhesion molecules disrupts the normal development of the lens cells. The third Specific Aim will test the hypothesis that mutant ¿A- or ¿B-crystallin disrupt normal lens protein homeostasis leading to abnormal protein degradation. Biochemical, cell biological and genetic studies will be performed. The results of these studies will provide new insights into molecular basis of lens development and cataract formation, and may promote the development of strategies to delay or prevent cataracts.