The long range goal of the proposed studies is to elucidate the mechanism of radiation cataractogenesis. To do so the work will focus on three aspects of the problem. 1. The site of the initial injury. 2. The nature of the injury. 3. The manner in which the injury is expressed as cataract. The hypothesis to be tested assigns the initial insult to the genome of the lens epithelial cell. The cataract is the result of the expression of that injury during lens fiber differentiation. The studies directed at the first question will include preferential sensitization of the DNA of lens cell subpopulation using BrdU substitution techniques. Endocrinological intervention experiments are designed to dissect the roles of growth and differentiation in the radiation response. Investigations will be conducted to attempt to confirm that the bird lens, heretofore thought to be radioresistant, does develop radiocataracts. It appears that the unique anatomy, which accounts for the exaggerated period before lens epithelial cells become fibers, is responsible, thus corroborating the role of the epithelium in radiation cataract development. Radiation genotoxicity will be assayed by sister chromatid exchange and chromosomal aberration analyses. Both cytogenetic methods have been adapted by our laboratory to lens research. In addition the distinctive nature of heavy particle irradiation (500 MeV Argon) will be fully exploited to clarify the nature of other damage at the cellular and subcellular level. Cell kinetic and cytopathological studies willl aim at characterizing the nuances of the manner in which the affected epithelial cells transduce the injury into a clinically detectable opacity. The work will focus on perturbations in the lens epithelial cell cycle and differentiation. The latter aspect will be monitored by analyzing possible effects on the cytoskeleton and the crystallins within individual cells known to be damaged. The findings will contribute greatly to our understanding of cortical cataractogenesis of varying etiology, including age, and will have direct application in radiation risk assessments from radiation therapy, occupational exposure and in the space program.
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