The most common form of inherited human blindness is retinitis pigmentosa, a family of disorders in which photoreceptor cells of the retina progressively degenerate and disappear over a period of years. The paucity of human donor tissues at early stages of these diseases and others, such as age-related macular degeneration, has led scientists worldwide to turn to similar retinal degenerations in laboratory animals. These animal models of the human diseases have and continue to play a pivotal role in vision research on the cellular mechanisms of photoreceptor degenerations and the development of potential therapeutic measures for these diseases. Among the various species with retinal degenerations, mice and rats have been used most extensively, primarily because of the experimental advantages of short gestation time;small size;powerful genetic control in the form of several readily available retinal degeneration mutants, multiple inbred and congenic strains with genetic controls;and the potential to carry out certain embryological and genetic procedures such as the production of experimental chimeras and transgenic animals. For most therapeutic studies in the areas of neuroprotection, drug delivery, transplantation and visual prostheses, the rat is the species of choice among rodents because an intermediate-sized eye is required, yet large numbers of genetically controlled animals are needed. The high costs to maintain animal colonies on individual grant budgets are beyond the means of most vision scientists, and most investigators do not have the time or expertise in mammalian genetics to develop or maintain various inbred, congenic and transgenic rat strains. Thus, the specific aims of this proposal are 1) to maintain breeding colonies of mutant rats that are appropriate for studies on various forms of inherited retinal degeneration, and 2) to distribute these animals and eye tissues to investigators who request them. These lines are 1) highly inbred Royal College of Surgeons (RCS) rats with inherited retinal dystrophy;2) three rat strains congenic with RCS that serve as genetic controls and with different eye pigmentation and rates of retinal degeneration;3) P23H mutant rhodopsin transgenic rat lines with 3 different rates of degeneration;and 4) S334ter mutant rhodopsin transgenic rat lines with 5 different rates of degeneration. The overall goal of this project is to facilitate research on retinal degenerations by producing, maintaining and distributing rat models necessary for this research. Based on past performance and the continued high use and demand for these animals, this colony and the distribution of animals will benefit scores of vision scientists and will have a major impact on research leading to the causes, prevention and treatment of retinal degenerative diseases. More than 90 current and pending grant projects are dependent upon this Retinal Degeneration Rat Model Resource established by the National Eye Institute in 1986.

Public Health Relevance

More than 6 million people in the United States have blinding diseases with no known cure that result from the death of photoreceptor cells in the eye. For most therapeutic studies in the areas of neuroprotection, drug delivery, transplantation and visual prostheses, the rat is the species of choice among rodents as an experimental model, because an intermediate-sized eye is required, yet large numbers of genetically controlled animals are needed. The goals of the research program are to maintain breeding colonies of all the known, well-characterized rat models (3 lines of P23H and 5 lines of S334ter rhodopsin transgenic rats and 4 lines of inbred and congenic RCS rat strains) and to distribute them to vision scientists for studies leading to the causes, prevention and treatment of retinal degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY006842-25
Application #
8585847
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1986-09-30
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
25
Fiscal Year
2014
Total Cost
$208,575
Indirect Cost
$73,575
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
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
Stiles, Megan; Qi, Hui; Sun, Eleanor et al. (2016) Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration. J Lipid Res 57:818-31
Orhan, Elise; Dalkara, Deniz; Neuillé, Marion et al. (2015) Genotypic and phenotypic characterization of P23H line 1 rat model. PLoS One 10:e0127319
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
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
Vollrath, Douglas; Yasumura, Douglas; Benchorin, Gillie et al. (2015) Tyro3 Modulates Mertk-Associated Retinal Degeneration. PLoS Genet 11:e1005723
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48
Kroeger, Heike; LaVail, Matthew M; Lin, Jonathan H (2014) Endoplasmic reticulum stress in vertebrate mutant rhodopsin models of retinal degeneration. Adv Exp Med Biol 801:585-92
Hiramatsu, Nobuhiko; Messah, Carissa; Han, Jaeseok et al. (2014) Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 25:1411-20
Li, Mei; Yasumura, Douglas; Ma, Aye Aye K et al. (2013) Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease. PLoS One 8:e56026

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