The retina provides an ideal system in which to examine the nature of the mechanisms involved in late onset degenerative diseases that may be related to aging. A great deal is known about the biochemistry involved in the photoreceptor cascade that converts light to electrical signals and there is a great deal known about the structure of the retina and its development and differentiation. By using transgenic animals in the past four years we have developed lines of animals that express dominant mutant forms of components of the phototransduction cascade and studied the effects of these mutations on photoreceptor function and on retinal degeneration. These systems provide us with an opportunity to examine the effects of aging on comprised retinal systems and compare these models with late onset retinal degeneration disease. In continuing this project, we will generate more sophisticated mouse models by using homologous recombination to disrupt and replace genes encoding specific major components of the phototransduction cascade and by using cell type specific promoters to generate reporter systems that respond to growth and differentiation factors in the retina. In addition to defining the role of the components of the phototransduction cascade in maintaining cells in the retina, we will also study the effects of growth factors on retinal cell differentiation and maintenance. We will use transplantation and transgenic techniques to generate animals that have cells that secrete different growth factors at different stages during retinal development and to study the effects of these factors on the degeneration and differentiation. In addition, we will use transgenic mice and the reporter group s that we developed in order to transplant cells into the retinas of new born and eventually mature animals in order to try to ameliorate the effects of retinal degeneration.
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