Transplantation of embryonic neural retina may some day be possible as a treatment for retinal diseases such as - macular degeneration and retinitis pigmentosa, but only after transplantation strategies are developed that result in appropriate functional connections of the transplant with the host retina that restore visual function. We have been developing and testing a transplant system which is providing considerable fundamental information that may be applied to solving these problems.Our experimental approach uniquely uses sheets of embryonic donor tissue which results in the development of ordered retina tissue that has the greatest potential of developing appropriate synaptic connections, and which elicits little or no immune responses within the central nervous system of the same species. We have shown that long-term embryonic retinal transplants grow neuronal processes which form synapses in the host retina, and that intact sheets of embryonic retina can be transplanted with minimal distortion and can develop parallel retinal layers. The immediate goal of this proposal is to test specific hypotheses about how intact sheets of embryonic neural retina can be transplanted to replace light-damaged host photoreceptor cells and to make functional connections between graft and host. The proposed studies assess embryonic rat and human intact-sheet retinal transplants in rats, using psychophysics, local electroretinograms, tracing methods and immunohistochemistry. Human embryonic transplants to light-damaged athymic rats will provide a testing model for the viability and differentiation capacity of human embryonic retina A behavioral test of visual sensitivity will be used to assess whether the transplants are functional and if so, to quantify improved vision. Later, more advanced visual capabilities can also be tested. Light-activated local electroretinograms will be included to confirm the psychophysical data. (2) Anatomical connections will be visualized by DiI-tracing from the transplants into the host in combination with retrograde fluorogold label of host ganglion cells. Labelled fibers will be mapped by three- dimensional analysis. Synapse formation of transplant fibers will be analyzed by electron microscopy. Transplant and host retinal cells will be identified by immunohistochemistry. Transplantation of embryonic retinal sheets provides the best model for studying synapse formation and the effects of trophic factors in preventing the progression of retinal degeneration. The restoration of even limited visual function holds the promise of ultimately restoring vision lost through disease or trauma.
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