This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In post-mitotic photoreceptor cells, there is a significant increase in cell death when metabolic activity in the retina increases. This, together with the high focal concentrations of mitochondria in photoreceptors and the very high blood supply to the choriocapillaris, suggests that there may be very little reserve in the energy supply to photoreceptor cells. The complex inter-relationships between photoreceptors, M 11er cells and retinal pigment epithelium add to the vulnerability in that failure of other cell types readily leads to secondary photoreceptor cell loss. It seems possible that photoreceptor cells live on a knife's edge, and that relatively mild insults can significantly increase the probability of cell death. On the other hand, a relatively modest benefit to the cell may reduce the chances of cell death sufficiently to have an important clinical impact on vision. Usher syndrome is a group of diseases with autosomal recessive inheritance, congenital hearing loss, and the development of retinitis pigmentosa, a hereditary disease that affects photoreceptor cells and causes blindness. The rd5/rd5 mouse has been identified as an animal model for Usher syndrome and linkage mapping suggests homology to Usher type I located on human chromosome 11 at p15. Growth factors such as pigment epithelium-derived factor (PEDF) and basic fibroblast growth factor (bFGF)and small molecules such as phenyI-N-tert-butylnitrone (PBN) have been shown to protect photoreceptors from degeneration in rat model and in culture. However, the mechanism(s) by which PEDF and PBN protect photoreceptors remains unknown. Because little is known about Usher Type I disease and currently, no treatment exists for such disease, it would be important to know whether photoreceptor degeneration in rd5/rd5 mouse can also be delayed or prevented by growth factors or small molecules. The overall goal of this proposal is to explore the role of growth factors and small molecules in photoreceptor protection in rd5/rd5 mice. The protection will be evaluated histologically by measuring the thickness of the outer nuclear layer and functionally by electroretinography. Proteomics and DNA-microarrays will be used to identify genes and proteins differentially expressed between homozygous (rd5/rd5) and normal heterozygous (rd5/+) mice with and without treatments. Western and Northern blot analysis will be used to quantitate the expression, and immunohistochemistry and in situ hybridization will be used to localize the expression. Any of our experimental regimes, which prevent the loss of photoreceptors in this mouse, would be extremely relevant to the therapeutic treatment of humans with Ushers and possibly other types of inherited retinal disorders.
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