Refractive eye development is a tightly coordinated process whereby visual input regulates growth of the eye in a process called "emmetropization". The emmetropization process is regulated by a vision-driven feedback loop in the retina and downstream signaling cascades in other ocular tissues, normally resulting in correct focal length of the eye and sharp vision. Failure of emmetropization leads to the development of refractive errors (i.e., farsightedness or nearsightedness). The prevalence of nearsightedness (myopia) in the U.S. population has increased from 25% to 44% over the last 30 years and reached epidemic proportions in Asia;however, very little is known about the genes underlying refractive eye development and how they interact with each other and with the environment to regulate refractive eye development. The efforts to uncover genetic factors underlying refractive error development are complicated by the difficulty with identification of chromosomal loci underlying diseases with large environmental contributions (such as common myopia) in humans. Validation and characterization of candidate genes regulating refractive eye development in traditional animal models of refractive eye development (such as monkeys, tree shrews and chickens) is also problematic because of limited information about their genomes and the lack of established techniques for targeted genome manipulation. We have recently demonstrated that mouse refractive eye development is fundamentally similar to that in other mammals, including humans. We have also developed a mouse model of myopia, which has all the features of human myopia. Here we present data that existing genetic variation in the laboratory mouse modulates refractive eye development yielding mouse strains with naturally occurring hyperopia, myopia and emmetropia. These mouse strains, in combination with the mouse model of myopia developed in our laboratory, well-established mouse QTL mapping and gene-targeting techniques, represent a novel powerful platform for studies of genetic mechanisms of refractive eye development using systems genetics approaches. Our central hypothesis is that refractive eye development in mice is regulated by strain-specific alleles of multiple interacting genes. Our long-term goal is to understand how genetic and environmental factors interact to guide refractive eye development and identify genetic factors responsible for the development of refractive errors. The objective of this application is to identify chromosomal loci, genes, and genetic networks underlying refractive eye development in the mouse model using systems genetics approaches. To achieve our objective, we will map chromosomal loci underlying refractive eye development in mice, identify strain-specific differences in genetic networks underlying strain-specific differences in refractive eye development in mice, and identify and prioritize candidate genes underlying refractive eye development in mice. The proposed studies will use the power of systems genetics and a new mouse model of myopia to provide the comprehensive overview of the genetic networks underlying refractive eye development and to identify genes responsible for the development of refractive errors. These studies will enhance our understanding of the signaling pathways underlying development of refractive errors, and will provide an experimental framework for the development of pharmacological means to treat and prevent myopia.
The prevalence of myopia has increased from 25% to 44% of the U.S. adult population in the last 30 years with the direct annual cost of refractive correction alone reaching $7.2 billion. Current treatment options are limited to optical correction using glasses, contact lenses or refractive surgery, which does not prevent progression of myopia or complications associated with the disease. Epidemiological data suggest that low-grade common myopia represents a major risk factor for a number of serious ocular pathologies such as cataract, glaucoma, retinal detachment, and myopic maculopathy, which is comparable to the risks associated with hypertension for stroke and myocardial infarction, and represents the seventh leading cause of blindness in the United States. The proposed studies will lead to the identification and characterization of chromosomal loci, genes and signaling pathways underlying the development of refractive errors, which will facilitate the development of novel therapeutic approaches to treat and prevent myopia.