The most common inherited disorder causing blindness in man is retinitis pigmentosa, a family of diseases in which photoreceptor cells of the retina degenerate slowly and progressively over a period of years, and pigmented cells move into the degenerating retina. Similar inherited diseases are found in several laboratory animals. The major long-term objective of our research program is to elucidate the cellular mechanisms that lead to photoreceptor cell death in hereditary retinal degenerations. Understanding these mechanisms should ultimately lead to therapies to retard or even prevent the loss of these cells. We propose to study the effects of 5 mutations that cause 6 different forms of inherited retinal degeneration. Thee animal models ar the RCS rat and the following mutant mice: retinal degeneration, nervous, Purkinje cell degeneration and retinal degeneration slow (both homozygous and heterozygous forms).
OUr specific aims are generally to define the phenotypic characteristics (i.e., cytopathologic features and sequence of changes that occurs in each of the mutants. To accomplish this we will use method s of quantitative light and electron microscopy, histochemistry and immunocytochemistry, as well as the application of these methods to the retinas of experimental chimeras. Analysis of he interphotoreceptor matrix will be a major focus of many of the studies. Mechanisms controlling normal turnover of the interphotoreceptor matrix will be addressed as well. The experimental chimeras will be used further to determine if some genetic defects can be ameliorated or reversed. In addition, the interphotoreceptor matrix will be examined in postmortem donor eyes of patients with different forms of retinitis pigmentosa. Lastly, a murine model will be sought for experimental studies on Usher's Syndrome, the major cause of combined deafness and blindness in the United States.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37EY001919-17
Application #
3483930
Study Section
Visual Sciences B Study Section (VISB)
Project Start
1978-07-01
Project End
1993-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
17
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
LaVail, Matthew M; Yasumura, Douglas; Matthes, Michael T et al. (2016) Gene Therapy for MERTK-Associated Retinal Degenerations. Adv Exp Med Biol 854:487-93
Chiang, Wei-Chieh; Joseph, Victory; Yasumura, Douglas et al. (2016) Ablation of Chop Transiently Enhances Photoreceptor Survival but Does Not Prevent Retinal Degeneration in Transgenic Mice Expressing Human P23H Rhodopsin. Adv Exp Med Biol 854:185-91
Kohl, Susanne; Zobor, Ditta; Chiang, Wei-Chieh et al. (2015) Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet 47:757-65
Vollrath, Douglas; Yasumura, Douglas; Benchorin, Gillie et al. (2015) Tyro3 Modulates Mertk-Associated Retinal Degeneration. PLoS Genet 11:e1005723
Chiang, Wei-Chieh; Kroeger, Heike; Sakami, Sanae et al. (2015) Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration. Mol Neurobiol 52:679-95
Alavi, Marcel V; Chiang, Wei-Chieh; Kroeger, Heike et al. (2015) In Vivo Visualization of Endoplasmic Reticulum Stress in the Retina Using the ERAI Reporter Mouse. Invest Ophthalmol Vis Sci 56:6961-70
Orhan, Elise; Dalkara, Deniz; Neuillé, Marion et al. (2015) Genotypic and phenotypic characterization of P23H line 1 rat model. PLoS One 10:e0127319
Murray, Susan F; Jazayeri, Ali; Matthes, Michael T et al. (2015) Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration. Invest Ophthalmol Vis Sci 56:6362-75
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48
Hiramatsu, Nobuhiko; Messah, Carissa; Han, Jaeseok et al. (2014) Translational and posttranslational regulation of XIAP by eIF2? and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 25:1411-20

Showing the most recent 10 out of 98 publications