The ultimate aim of this research is to find genes that influence the severity and/or course of human retinal degenerative diseases; specifically, to find the alleles of such genes that reduce the severity and slow down the progression of disease. The approach is to first find retinal degeneration modifying genes in mouse models. The work involves two models: mice that show differences relative to strain type in: 1) age-related retinal degeneration; and 2) mutation induced or inherited retinal degeneration. The study follows an experimental plan with a specific order. The first phase involves genetic crosses between the mouse strains that show differences in retinal degeneration. The second, analysis of the data with quantitative genetics programs to identify the multiple chromosomal loci containing retinal degeneration modifying genes. The third, breeding of mouse strains with modifier gene chromosomal loci from one strain bred into the background of the other strain in order to reduce the area in which to search for the modifier genes. The fourth, to identify candidate genes in the modifier gene chromosomal loci from the databases, and fifth to study the genes by various molecular biological and genetic means. The sixth, to test putative modifier genes by transgenic studies. For the age-related retinal degeneration studies, the work continues at the third phase. For the mutation-induced retinal degeneration studies the work begins with the first phase. The discovery of the identity and mechanism of action of these modifier genes will open avenues of study leading to new gene or pharmaceutical therapies for human retinal degenerations. Considering that there are nearly 160 different primary causes of human retinal degeneration so far known, and that age-related macular degeneration is a complex genetic disease with multiple susceptibility genes, it would be of great benefit if any one or a few of these modifying genes protects against retinal degenerations of several different causes. This would make therapeutic approaches simpler. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY013280-05A1
Application #
7029385
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
2001-04-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$209,527
Indirect Cost
Name
Loyola Marymount University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072946239
City
Los Angeles
State
CA
Country
United States
Zip Code
90045
Gorbatyuk, Marina S; Knox, Tessa; LaVail, Matthew M et al. (2010) Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc Natl Acad Sci U S A 107:5961-6
Ogando, Diego G; Dahlquist, Kam D; Alizadeh, Mitra et al. (2010) Candidate genes for chromosomes 6 and 10 quantitative trait loci for age-related retinal degeneration in mice. Mol Vis 16:1004-18
Danciger, Michael; Ogando, Diego; Yang, Haidong et al. (2008) Genetic modifiers of retinal degeneration in the rd3 mouse. Invest Ophthalmol Vis Sci 49:2863-9
Danciger, M; Yang, H; Ralston, R et al. (2007) Quantitative genetics of age-related retinal degeneration: a second F1 intercross between the A/J and C57BL/6 strains. Mol Vis 13:79-85
Danciger, Michael; Yang, Haidong; Handschumacher, Lisa et al. (2005) Constant light-induced retinal damage and the RPE65-MET450 variant: assessment of the NZW/LacJ mouse. Mol Vis 11:374-9
Danciger, Michael; Lyon, Jessica; Worrill, Danielle et al. (2004) New retinal light damage QTL in mice with the light-sensitive RPE65 LEU variant. Mamm Genome 15:277-83
Danciger, Michael; Lyon, Jessica; Worrill, Danielle et al. (2003) A strong and highly significant QTL on chromosome 6 that protects the mouse from age-related retinal degeneration. Invest Ophthalmol Vis Sci 44:2442-9