: Photoreceptors are designed to retain functional and structural integrity over the entire lifespan of an animal, yet they are intrinsically unstable and vulnerable. Any changes that alter the composition of the signal transduction cascade, influence the energy metabolism or the oxygen tension or disturb the phagocytotic process by the retinal pigmented epithelium, can lead to photoreceptor degeneration. Photoreceptors have developed self-protective mechanisms involving growth factors and antioxidants to ensure survival and function, Research has tried to tap into these self-protective mechanisms and use growth factors to treat experimental photoreceptor degeneration. However brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor, the two most widely used factors, do not act on the photoreceptors directly, but indirectly through retinal Mueller glia cells (Wang et al., 1999; Rohrer et al., 1999). But progress in this field is limited by the need to know the identities of the rescue factors, and what are their target genes in the photoreceptors. Our approach is twofold. We wish to find target genes of BDNF stimulation and common genes that underlie both photoreceptor degeneration and neuroprotection, using gene expression arrays (GEAs). GEAs allow screening the expression levels of thousands of genes within one tissue. The tissue should contain a small number of different types of neurons and few glial cells to avoid diluting out interesting transcripts. The mouse retina is a very good model system, as rod photoreceptors outnumber other cells by approximately 3.5:1 (Jeon et al., 1998). Thus, hypothetical target genes in rods would be expressed in three-quarters of the cells. (1) To assess the involvement of BDNF acting through its receptor TrkB in photoreceptor development and function, we have developed a trkB knock-out mouse, which shows signs of photoreceptor cell malformation and degeneration. We used Affymetrix gene chips, comparing wild-type with trkB knock-out retinas, in order to identify potential target genes of TrkB stimulation. (2) If photoreceptors have a finite repertoire of mechanisms to respond to insult, the genes activated under different insult conditions should be similar. We propose to analyze retinas from three photoreceptor degeneration models, the rd and rds mouse as well as the light-damage model, all which have been reported to benefit from neuroprotection through cytokines, using this strategy. We expect to isolate common downstream target genes that are activated both during degeneration and neuroprotection.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Visual Sciences C Study Section (VISC)
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Mariani, Andrew P
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Medical University of South Carolina
Schools of Medicine
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