Many diseases that ultimately lead to blindness are caused by the degeneration of photoreceptor (PR) cells. Cones typically die after rods, with kinetics somewhat dependent upon the particular disease. Rod loss followed by cone loss is also seen in cases where a genetic etiology has not been established, as in some forms of macular degeneration. While humans are able to function quite well without rods, the loss of cone-mediated vision is devastating. The reason(s) that cones die in these cases is unknown. However, since cone loss can be initiated by events that are not intrinsic to cones, these events must include some type of cell-cell interaction, perhaps including the action of a secreted molecule(s). Such a process may be susceptible to interruption through the application of a pharmacological or a cell based therapy. In addition to progressive diseases such as retinitis pigmentosa, there is a mouse model, the cyclin D1 knock-out (KO) mouse, in which degeneration is arrested. The cause of PR death, as well the cause of the arrest, are unknown. This model may provide some insight into how degeneration can be arrested in progressive diseases. We are seeking to use retinal microarrays to define the gene expression changes that accompany PR death in mice, with an emphasis on the events that lead to cone death. In addition, we will characterize the gene expression changes that accompany the arrest of PR degeneration in the cyclin D1 mutant. We further plan to characterize the expression patterns of such genes in normal and pathological tissue. Finally, we will explore the function of some of these genes using genetic approaches in mice. ? ?
