The Lens and Cataract Biology Section investigates aspects of the normal biology of the ocular lens and the molecular mechanisms underlying cataractogenesis, with the ultimate goal being the development of therapeutic modalities to prevent or delay cataract development. ? ? ? The major project for the Section, conducted in collaboration with Dr. Debasish Sinha of the Wilmer Eye Institute, is the characterization of a line of mutant Sprague-Dawley rats which exhibit a number of abnormalities in ocular development. The mutation which we have named Nuc1 was first studied because heterozygotes have dense nuclear cataracts that are present from birth. Homozygotes have ruptured lenses and microphthalmia by the time of birth. Histological analysis has subsequently revealed that in addition to the lens abnormalities, these animals have other developmental problems. The retina is abnormally thick with more cells in the various layers then in the wildtype rat and there is delayed maturation of the retina. In addition, the regression of the embryonic vasculature, including the pupillary membrane and hyaloid system, is delayed significantly in Nuc1. We believe that all of these developmental problems may result from an impairment or inhibition of apoptosis. The regulation of cell numbers in the retina and the maturation of the retina are dependent upon programmed cell death as is the vascular regression process. In the lens of Nuc1 rats there is a failure of the denucleation process which normally occurs when lens fiber cells become mature. This denucleation, while not true programmed cell death, is believed to be an apoptotic- like process. In order to identify the particular gene that has mutated and to ultimately elucidate the molecular mechanisms underlying the Nuc1 phenotype a genome wide linkage analysis is currently in progress. Concurrently, microarray and proteomic studies comparing the Nuc1 retina with wildtype at various ages are also being conducted.
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