Trophic interactions among sensory cells, neurons and supporting cells play an important role in the development and maintenance of sensory function. Loss of any one component may lead to atrophy of other cells, resulting in sensory deficit. Photoreceptor loss is the primary cause of visual impairment in several retinal degenerative diseases such as retinitis pigmentosa and macular degeneration. Sensory impairment resulting from degeneration of neural tissue was once considered irreversible. New possibilities are being raised as understanding of biochemical and molecular mechanisms of photoreceptor degeneration increases in animal models such as the rd (retinal degeneration) mouse. Furthermore, recent neural transplantation efforts related to degenerative brain diseases such as Parkinson's, Huntington's and Alzheimer's have stimulated research on neurosensory transplantation. Recently, this lab has presented evidence that normal photoreceptors transplanted from healthy mice can rescue cone photoreceptors in the rd mouse. This is the first instance of neurosensory rescue in an animal model relevant for a human sensory dystrophy. This proposal is based on the hypothesis that normal rod photoreceptors have a trophic effect on cone photoreceptors and supporting cells such as retinal pigment epithelium (RPE). The long term goal of this research is to develop an understanding of the molecular changes that underlie the secondary degeneration of cones and RPE in the rd mouse and to develop methods to prevent or minimize this loss. To achieve these goals, (I) normal mouse photoreceptors will be transplanted into the rd mouse followed by statistical and morphometric analysis to measure the effect of the transplanted cells on the survival of host cells, (2) an organ culture system will be developed with normal and dystrophic retinal tissue to simulate the in vivo model and (3) the organ culture system will be manipulated with trophic factors known to mediate sensory cell growth to better understand what molecular mechanisms are involved in maintenance and survival of sensory and supporting cells. The proposed re-entry training program builds on previous training by reestablishing both current knowledge of retinal research and technical expertise in light and electron microscopy. New training will emphasize knowledge of neurotrophic factors and cell and organ culture techniques. These elements will be use to build a research program focusing on trophic interactions between neural and support cells in the visual system.
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