Approximately 50 million people worldwide are blind and ~150 million are significantly vision impaired. Except for trauma and infections, the majority of human eye diseases are genetic in nature. The number of human loci causing retinal disease is ~ 9-fold greater than the number of available associated animal models, indicating a large gap in models for studying diseases that are known to occur in humans. The mouse with its well-developed genetics, similarity to human physiology and anatomy, and accessibility for genetic manipulation is a widely accepted and useful model system. Mouse models have been used to provide candidate genes for human diseases, tissues for study throughout development and disease progression, and test systems for therapies. They are also an ideal platform to identify and dissect biologically relevant pathways through genetic means. In the last funding cycle, we generated >60 models with ocular defects. We have identified the molecular basis of 20 of the mutant lines from which many unique insights were obtained. In this application, we plan to complete the molecular and phenotypic characterization of the 40 remaining lines (Aim 1) and make them available to the scientific research community. Extending our ongoing genetic studies, we propose to use a sensitized chemical mutagenesis screen to reveal pathways important in the Crumbs1 pathway (Aim 2). While there are many strategies available to identify interacting factors of primary genes/mutations, chemically induced mutations have the advantage that they will allow for the unbiased identification of a wide array of genes that interact with CRUMBS1. These genes may explain the plethora of diseases associated with mutations within Crumbs1. It will also allow for identification of factors that interact with the extracellular domain of CRUMBS1, an endeavor that has been intractable by the current available methods. In the present application, we will screen ~10,000 mutagenized G3 Crumbs1rd8/rd8 mice by indirect ophthalmoscopy to identify mutants that present with an altered Crumbs1drd8 fundus phenotype. The molecular bases of these factors will be identified and through the use of standard immunohistochemical methodologies in conjunction with the use of 4Pi microscopy, we will examine the effects of the newly identified genes/mutations on the CRUMBS1 pathway. Successful conclusion of this proposal will not only generate well characterized ocular models, but will potentially identify entry points into the CRUMBS1 pathways as well as other molecules that are important in eye biology and afford us the opportunity to build and test hypotheses about normal ocular function and disease pathology.

Public Health Relevance

Virtually all non-traumatic and non-infectious ocular diseases in humans are genetic in origin or have a strong genetic component;genetic disorders account for more than 95% of common eye diseases. Identification of disease causing genes and animal models to study the disease progression and pathological consequences of mutations is extremely important. Many eye diseases in humans, if identified early enough, may be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights to new treatment regimens and the models can then be used to test those therapeutics. Finally, knowledge of the disease causing genes and the pathways in which they function may lead to an understanding that is critical in defining therapeutic targets for prevention of vision impairment and loss.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Chin, Hemin R
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Jackson Laboratory
Bar Harbor
United States
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Kong, Yang; Zhao, Lihong; Charette, Jeremy R et al. (2018) An FRMD4B variant suppresses dysplastic photoreceptor lesions in models of enhanced S-cone syndrome and of Nrl deficiency. Hum Mol Genet 27:3340-3352
Charette, Jeremy R; Earp, Sarah E; Bell, Brent A et al. (2017) A mutagenesis-derivedLrp5mouse mutant with abnormal retinal vasculature and low bone mineral density. Mol Vis 23:140-148
Krebs, Mark P (2017) Using Vascular Landmarks to Orient 3D Optical Coherence Tomography Images of the Mouse Eye. Curr Protoc Mouse Biol 7:176-190
Greenwald, Scott H; Charette, Jeremy R; Staniszewska, Magdalena et al. (2016) Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease. Am J Pathol 186:1925-1938
Charette, Jeremy R; Samuels, Ivy S; Yu, Minzhong et al. (2016) A Chemical Mutagenesis Screen Identifies Mouse Models with ERG Defects. Adv Exp Med Biol 854:177-83
Ji, Xiaojie; Liu, Ye; Hurd, Ron et al. (2016) Retinal Pigment Epithelium Atrophy 1 (rpea1): A New Mouse Model With Retinal Detachment Caused by a Disruption of Protein Kinase C, ?. Invest Ophthalmol Vis Sci 57:877-88
Saksens, Nicole T M; Krebs, Mark P; Schoenmaker-Koller, Frederieke E et al. (2016) Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity. Nat Genet 48:144-51
Zhao, Lihong; Spassieva, Stefka; Gable, Kenneth et al. (2015) Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration. Proc Natl Acad Sci U S A 112:12962-7
Chang, Bo (2015) Survey of the nob5 mutation in C3H substrains. Mol Vis 21:1101-5
Maddox, Dennis M; Collin, Gayle B; Ikeda, Akihiro et al. (2015) A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia. Invest Ophthalmol Vis Sci 56:3776-87

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