One hallmark of the adult human central nervous system is that damage is permanent. Neurons that die as a result of stroke or trauma are never replaced. In striking contrast, in the retina of adult teleost fish neuronal death stimulates neuronal regeneration and recovery of function. Our understanding of neuronal regeneration in fish is still only rudimentary. Little is known about the cellular, molecular or genetic events that underlie the ability of this animal to repair injuries to its brain. The broad objectives of the research described here are to understand in detail the cellular and molecular sequelae of neuronal injury and regeneration in the retina of the goldfish. Using both the normal and injured/regenerating retina of fish, five studies are proposed that will: 1) use organ culture and immunocytochemical techniques to identify peptide growth factors that control the proliferation of neuronal progenitors; 2) use in situ hybridization and receptor binding autoradiography techniques to identify cells that produce the peptide growth factor, insulin-like growth factor-I (IGF-I and the IGF-I receptor, respectively; 3) use in situ hybridization and immunocytochemistry to characterize the expression patterns of known retinal homeobox genes; 4) use quantitative morphometry to assess the regeneration of the foveated retina in the lemon wrass; and 5) using intracellular injections of Neurobiotin to characterize the formation of gap junctions between regenerated neurons and between regenerated neurons and extant cells in intact retina. Retinal lesions will be produced surgically by removing a small piece of retina or by intraocular injections of the metabolic poison, ouabain. Detailed knowledge about neuronal injury and retinal repair in the goldfish will contribute to our general understanding of the cellular consequences of neuronal injury in the mammalian CNS and may contribute to devising novel therapeutic approaches for treating retinal injuries in humans.
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