The goal of our research program is to identify molecules that are necessary for normal retinal development and function by using mouse models as an entry point for gene identification and for elucidation of gene function and mechanisms underlying disease pathologies. This renewal application focuses on three unique models, retinal degeneration 7 (rd7), retinal degeneration 6 (rd6) and retinal dysplasia 1 (rdp1), which clinically all exhibit retinal spotting and strikingly similar retinal dysplasia that manifest as folds and rosettes of the PR layer early in life. rd6 and rd7 also exhibit progressive late-onset panretinal degeneration. Interestingly, double mutants homozygous for both rd6 and rdp1 show an earlier and more severe retinal dysplasia than mice homozygous for rd6 alone, suggesting an interaction between the two mutations. Clinically these mutants are most reminiscent of flecked retinal disorders in humans. In this proposal, we build our studies upon what we have learned previously. We are currently at different stages in the investigation of each model. For rd7, we know the gene, Nr2e3, a member of the steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors, and here, we propose to further examine its role in cone cell differentiation and the mechanism for the apparent increase in S-opsin immunoreactive cells. We also plan to identify co-regulators and downstream targets of this Nr2e3 to determine the context in which it functions. For rd6, we are in the final stages of positional cloning and are examining candidates. To assist in choosing candidates, we are further defining the rd6 phenotype. We plan to make aggregation chimeras to determine the site of action of the mutant gene and to do autoradiographic studies to determine if the reduction in phagosomes may be affected by alterations in outer segment (OS) renewal or shedding. In the case of rdpl, a gene that appears to interact with rd6 to cause a more severe retinal phenotype and is histologically similar to the rd7 mutant, we are in he initial stages of mapping. We will construct a genetic map of rdp1 with the goal of positionally cloning it. Finally, we will determine the temporal and spatial expression of rd6 and rdp1 by in situ and by immunohistochemistry once the genes are identified. Identification of disease-causing genes and animal models is extremely important. Knowledge of the disease-causing genes may lead to an understanding of pathways that are critical in maintaining normal function of the eye and perhaps, may identify therapeutic targets for prevention of vision loss.
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