This is the second revision of a proposal to create mouse models of the human retinal diseases caused by mutations in the peripherin/rds gene. The applicant will accomplish this by first characterizing the promoter region of the peripherin/rds gene (hence called rds), as proposed in specific aim 1. The temporal and tissue regulation of the promoter will be tested by determining the capability of promoter fragments to drive reporter gene expression in transgenic mice.
In specific aim 2, the applicant will generate transgenic mice in which synthesis of bovine rds is under control of the rds promoter or other rod and cone specific promoters. Both the normal bovine gene and two mutant bovine rds genes will be examined. With respect to the mutant genes, the mutants were selected to have molecular changes identical to ones found in human diseases: one causes macular dystrophy in humans and the other causes autosomal dominant retinitis pigmentosa in humans. A new specific aim three has been added to address the issue if gene haploinsufficiency is responsible for the disease. Transgenic mice will be bred on +/+, rds/+ and rds/rds genetic backgrounds to investigate the mode of action of the mutant gene. The transgenic mice will be characterized by histological and physiological methods designed to gain insights into the effects of the mutant gene on the photoreceptor cell biology. Finally, tests are proposed to determine if mutant rds protein can bind to the ROM1 protein.
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