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Research Aim 3

Research Aim 3

Investigations aimed at understanding why retinal degenerations occur and how they might be treated, with particular emphasis on neurotrophic factors.

 Mutations in several photoreceptor-specific genes have been demonstrated to cause retinal degenerations. Recently, mutations in two genes that are differentially expressed in the RPE have been found to cause retinal degenerations. It is likely that there are many more RPE-specific genes that when mutated, cause retinal degeneration. In collaboration with the laboratory of Don Zack, our laboratory is attempting to identify genes that are differentially expressed in the RPE or retina, screening them for mutations in patients with retinal degenerations, and trying to determine the function of the genes by a variety of techniques, including targeted disruption by homologous recombination. One interesting gene that has been identified is a mammalian homolog of a Drosophila gene, rdgB, that when mutated causes retinal degeneration .

Apoptosis of photoreceptors occurs in several types of retinal degeneration and neurotrophic factors delay and decrease photoreceptor cell death in animal models of retinal degeneration. This suggests a possible therapeutic role for neurotrophic factors. Our laboratory is working to identify which neurotrophic factors act endogenously to promote photoreceptor and/or RPE survival. Photoreceptor-specific expression of dominant-negative fibroblast growth factor (FGF) receptors results in degeneration of photoreceptor cells, suggesting that one or more FGF acts as a survival factor in the outer retina.


REFERENCES

11. Chang JT, Milligan S, Li Y, Chew CE, Wiggs J, Copeland NG, Jenkins NA, Campochiaro PA, Hyde DR, Zack DJ: Mammalian homolog of drosophila retinal degernation B rescues the mutant fly phenotype. J Neurosci 1997,17:5881-5890

12. Campochiaro PA, Chang M, Ohsato M, Vinores SA, Nie Z, Hjelmeland L, Mansukhani A, Basilico C, Zack DJ: Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor. J Neurosci 1996,16:1670-1688

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