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. One model system we use to study the induction and prevention of cataract is the organ cultured lens. Dr. Madhumita Ghosh, who recently left the group to return to India, studied cellular proliferation and differentiation in the cultured test lens. She found that lens epithelial cells do continue to divide in culture, but that differentiation of epithelial cells into lens fibers is arrested. The net result is a failure of the cultured lens to grow. The lens culture system may provide advantages for the study of the factors regulating fiber cell differentiation over the systems which are currently used, i.e. lens epithelial cell culture, epithelial explants, and transgenic mice. In a series of studies initiated by Dr. Fred Bettelheim before his untimely death, we have continued to analyze the macromolecular components of the vitreous with respect to their regional distribution. Using dynamic light scattering, viscosity measurements, and proteomic analysis, we have found differential distribution of hyaluronan and of protein populations in normal human vitreous. Interestingly, we have found that major changes are present in these distribution patterns in eyes which have had cataract surgery. Such eyes also have significant levels of lens crystallins present in the anterior vitreous. The first paper on this work is currently in press and a second has been submitted for publication. A 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 we have undertaken a genome wide linkage analysis. This will be greatly facilitated by the recent publication of a high quality draft of the rat genome sequence.
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