This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our long-term goal is to understand the biological mechanisms of photoreceptor generation and maintenance, which will enable us to identify novel targets that may be amenable for improved treatment strategies. Our studies have focused on uncovering the transcriptional networks that are directed by the nuclear receptor gene Nr2e3 to modulate photoreceptor development and function. While many past studies have focused on the role of Nr2e3 in the developing retina, its high expression in the adult retina suggests an important function for Nr2e3 in mature photoreceptor cells as well. Furthermore, recent clinical reports have demonstrated that mutations in Nr2e3 not only account for the retinal degeneration observed in patients with enhanced S-cone syndrome (ESCS), but also account for 1-2% of autosomal dominant retinitis pigmentosa, a disease that typically leads to severe visual impairment in early adulthood progressing to severely limited vision or blindness by the fourth or fifth decade of life. We hypothesize that while the rd7 mouse serves as a good model for the excess blue cone cells contributing to the ESCS phenotype, the Nr2e3-Crerho mouse generated for this current study may provide a better model to recapitulate Nr2e3-associated retinitis pigmentosa and retinal degeneration due to loss of Nr2e3 function in the mature retina. With this new mouse model, we are able to study the defects associated with loss Nr2e3 in adult photoreceptor cells without affecting retinal development. We have thus revised this application to focus on the role of Nr2e3 in the mature retina and determine the extent to which loss of Nr2e3 in the mature retina contributes to the rd7 phenotype.
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