Retinal degenerative diseases can be broadly categorized by the anatomical location of the clinically manifested abnormalities. Degeneration in the group of diseases known as retinitis pigmentosa typically proceeds in a peripheral to central gradient. Macular degeneration, in contrast, affects, as the name indicates, the central region of the retina. Macular degeneration causes a loss in central vision, color vision, contrast sensitivity and fine visual discrimination. There is currently no cure for macular degeneration. Treatment for age-related macular degeneration (AMD) and its neovascular complications is hampered by a lack of relevant animal models for macular degeneration or macular dystrophies. Progress in identification of genes causing macular degeneration lags behind that in identifying genes causing retinitis pigmentosa. Recently, however, over six mutations have been detected in the TIMP-3-encoding gene (TIMP-3) in patients with Sorsby's fundus dystrophy (SFD). SFD is a degenerative disease that affects the macula with particular severity. With the identification of a gene defect causing macular degeneration, it becomes possible to generate (an) animal model(s) of the disease and to use these to define the molecular mechanisms which lead to the pathogenic findings. The applicants have recently identified the human TIMP-3 promoter region. Using this to drive mutated versions of a human TIMP-3 cDNA, mice transgenic for mutant human TIMP-3 have been generated. These mice appear to possess several abnormalities observed in SFD patients, including a relatively thick layer of sub-retinal pigment epithelium (RPE) deposits across the entire retina and defects in Bruch's membrane which expand in size over time. Control mice transgenic for wild-type human TIMP-3 have normal retinas. The research proposed here aims to further characterize these transgenic mutant TIMP-3 mice. In addition, using the Cre/lox recombination system, additional lines of mice containing RPE-specific or global TIMP-3 knock-outs will be generated. The pathogenic mechanisms observed in each of the lines of genetically altered mice (and in lines derived from crossing them) will be assessed. The characterization of the pathogenic basis of SFD could suggest therapeutic approaches for treating this disease and other forms of macular degeneration.
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