The long-term objective of this proposal is to characterize, chromosome map and isolate genes that may be involved in inherited retinal degenerations affecting animals and humans. Knowledge about the genes that are responsible for these diseases may increase our understanding of the process of pathogenesis and in addition, it may help to develop studies on how to control or even arrest the expression of the abnormal genes. The rd mouse model of retinal degeneration will be studied first. the basic strategy involves the development of a novel probe consisting of photoreceptor-enriched cDNAs which will allow selection of low abundance photoreceptor-specific clones from a normal mouse retinal cDNA library. These clones will be re-screened with probes consisting of rd adult retinal cDNAs and rd 9-11 day-old retinal cDNAs to pinpoint rd candidate genes. After Northern analysis of developing rd and normal mouse retinal RNAs with the rd candidate cDNAs to determine any differences between the rd and normal mRNAs, the mouse chromosome location of each potential rd cDNA will be determined and, if on chromosome 5, its specific position within this chromosome will be established. the nucleotide and reduced amino acid sequences as well as the genomic organization of the rd candidate genes and their in vitro transcription and translation will then be determined. Final proof of the identify of the rd gene with cloned gene will require correcting the rd phenotype. Experiments involving transgenic mice will be planned for the future but are not within the scope of this application. Isolated photoreceptor-specific cDNAs will be used in human studies to search for alterations in the patterns of RFLPs in families affected with any of the different types of retinitis pigmentosa. To carry out the proposed work, methods currently used in Molecular Biology will be employed. These studies will add to the knowledge of the molecular properties of normal and abnormal retinas since in addition to the rd gene other photoreceptor-specific genes may be characterized.
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