Detachment of the neural retina from the retinal pigmented epithelium induces a cascade of events detectable within minutes through the activation of early response genes. This leads to the """"""""retinopathy of detachment"""""""" (RD), a series of specific cellular events which have been detailed over the past funding period. This includes the death of some receptors by apoptosis, the """"""""deconstruction"""""""" of surviving photoreceptor cells so that they assume a more primitive structure, changes in gene expression in photoreceptors and Muller cells (and other retinal cells as well), the proliferation of all non-neural cell types in the retina, and significant growth of Muller cells within and outside their normal retinal boundaries. Visual recovery even after successful reattachment is often less than optimal, especially if the macula is involved. Retinal detachments have serious visual consequences and are a complication of several retinal diseases as well as part of experimental therapies for blinding diseases: foveal translocation, retinal transplantation and subretinal injections of vectors for transfection of retinal cells. Thus, defining the biological mechanisms underlying the responses to detachment and reattachment and finding methods to optimize recovery of the retina would seem to be of clear medical significance. This renewal application uses the investigator's established feline model of detachment/reattachment to study the ability of reattachment to stop or reverse fundamental cellular changes induced by detachment; to further study the use of neurotrophins such as CNTF and hyperoxia as ways to mitigate the degenerative effects of detachment or promote recovery after attachment; and to study the potential role of IL-1 and its receptor antagonist (IL-1ra) in the response to detachment. It is known that cone photoreceptors react differently to detachment than rods, but the study of cones in cat is difficult, and prohibitive in primates. The applicant proposes to develop a detachment/reattachment model in the California ground squirrel, a species with a retina compromised of about 85 percent cones, that is readily available, and that has been used extensively in vision research. The applicant will determine the feasibility of using ERG measures as a means of correlating the physiological and structural recovery of cone photoreceptors. The applicant believes that the use of this model will aid in understanding the responses of cones and to better determine if treatments (e.g., neurotrophins, hyperoxia) that mitigate the effects of detachments in rod-dominated retinas will do so in a cone-dominant retina as well. The applicant believes this information will provide a greater understanding of the retina's responses to injury, and may lead to ways of improving visual recovery in humans.
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