This project has focused on finding new mouse models of ocular disease, mapping and identifying the causative genes, and phenotyping the disorders. The project has been an ongoing, highly productive collaboration between an academic Ophthalmologist (subspecialty: ophthalmic genetics and retinal dystrophy) and clinical electrophysiologist at UCLA, and mammalian geneticists at the Jackson Laboratory (TJL). Our program discovers and characterizes new mouse models of ocular disease, which are clinically relevant to human eye diseases. Because there is high homology between the human and mouse genomes, estimated to be 90-95%, findings in mouse normally have a very high likelihood of having validity in human. Mouse models of inherited ocular disease allow for rapid genetic analysis, pathophysiologic characterization, and lead to a quicker understanding of disease processes. Models are important because human eye tissues are seldom available for studies in a reliable fashion. In the current grant period, we have found 22 new mouse models of eye disease [Table 1], identified three genes for retinal degeneration (rd10, rd12, cpf11), one gene (Vldlr, a targeted mutation) associated with subretinal and choroidal neovascularization (CNV), and three genes for cataracts (Lop12, Nm1853, Nm3062). We mapped 17 new eye mutant genes (Table 2) and 10 ocular cDNA clones (Table 3), published 18 papers and 12 abstracts. As of this renewal, this project has discovered 96 mouse models of ocular diseases, and mapped 52 of them to mouse chromosomes (see Appendix, Table 1), 44 of them have not yet been mapped (see Appendix, Table 2). One of the successful aims of our project has been to redesign human clinical testing techniques so that they can be applied to mouse, giving comparable data to human. We have successfully developed new techniques for electro-physiologic testing in mouse including a standardized cone and rod ERG, which is now widely used, multifocal ERG testing, sweep VECP for measuring visual acuity in mouse, and fundus photography and fluorescein angiography of mouse retina.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY007758-16
Application #
6891510
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Chin, Hemin R
Project Start
1988-08-01
Project End
2008-07-31
Budget Start
2004-05-01
Budget End
2004-07-31
Support Year
16
Fiscal Year
2003
Total Cost
$206,403
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ozel, A Bilge; Moroi, Sayoko E; Reed, David M et al. (2014) Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet 133:41-57
Thompson, Debra A; Khan, Naheed W; Othman, Mohammad I et al. (2012) Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15. PLoS One 7:e35865
Lu, Ying; He, Shirley; Jia, Lin et al. (2010) Two mouse models for recoverin-associated autoimmune retinopathy. Mol Vis 16:1936-48
Pang, Ji-Jing; Alexander, John; Lei, Bo et al. (2010) Achromatopsia as a potential candidate for gene therapy. Adv Exp Med Biol 664:639-46
Pang, J; Boye, S E; Lei, B et al. (2010) Self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration in two models of Rpe65 deficiency. Gene Ther 17:815-26
Lu, Ying; Jia, Lin; He, Shirley et al. (2009) Melanoma-associated retinopathy: a paraneoplastic autoimmune complication. Arch Ophthalmol 127:1572-80
Chang, Bo; Grau, Tanja; Dangel, Susann et al. (2009) A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A 106:19581-6
Anderson, Michael G; Hawes, Norman L; Trantow, Colleen M et al. (2008) Iris phenotypes and pigment dispersion caused by genes influencing pigmentation. Pigment Cell Melanoma Res 21:565-78
Pang, Ji-Jing; Boye, Sanford L; Kumar, Ashok et al. (2008) AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEbeta mutation. Invest Ophthalmol Vis Sci 49:4278-83
Chang, Bo; Mandal, Md Nawajes A; Chavali, Venkata R M et al. (2008) Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene. Hum Mol Genet 17:3929-41

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