Primary open-angle glaucoma (POAG) is a leading cause of blindness in the United States. In many cases, the disease is characterized by an elevation of intraocular pressure (IOP), progressive changes in the appearance of the optic disc and retinal nerve fiber layer, and visual field defects. Over the past several years, a number of studies have described the degenerative effects that chronic elevation of IOP and glaucoma have on fibers in the optic nerve, as well as the concomitant loss of ganglion cells that occurs within the retina itself. More recently, the applicants have combined the monkey model of experimental glaucoma with intracellular staining techniques to examine the morphological changes that characterize glaucomatous neuropathy at the single cell level. These studies showed, for the first time, that the earliest signs of glaucoma-related retinal ganglion cell (RGC) degeneration involves structural abnormalities associated with the dendritic arbors of these neurons. Since retinal ganglion cells receive all of their input from more distal retinal elements through their dendrites, abnormalities in dendritic structure suggest a reduction in synaptic efficacy, and early fractional deficits at the single cell level. A primary goal of the studies proposed here is to use combined anatomical and electrophysiological techniques to determine the extent to which glaucoma-related changes in ganglion cell structure might correlate with changes in ganglion cell function. A second important outcome of the investigator's previous years of work was the finding that morphological changes at the level of the cell body occur later than those at the dendritic tree. This suggests that there is a """"""""window of opportunity"""""""" during which the application of neuroprotectants to the diseased visual system might serve to slow or reverse ganglion cell death. Thus, a second goal of the proposed studies is to determine, using a cat optic nerve crush model of retinal ganglion cell atrophy, the extent to which different doses, delivery routes, and delivery rates of brain-derived neurotrophic factor (BDNF), a known neuroprotectant in the small rat eye, might also serve to enhance the survival of ganglion cells in primate-sized eyes and their primary target neurons in the thalamus of the brain.
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