Retinal mechanisms of refractive development

Emory University, Atlanta GA

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Myopia is the leading cause of vision impairment worldwide and is predicted to affect half of the global population by 2050. Although widely available, optical corrections such as glasses and contacts do not treat the underlying causes of myopia, resulting in millions of people being at an increased risk of developing blinding diseases later in life from retinal detachment and degeneration, glaucoma, and cataracts. Currently, it is known that a combination of complex genetic and environmental factors contribute to myopia development. For example, parental myopia increases the risk of myopia in children, and ambient light level exposure strongly correlates with myopia susceptibility. However, the genetic landscape that influences myopia is highly polygenetic and the mechanisms that drive changes in the retina, choroid, and sclera, which ultimately alter refractive error, remain elusive. In this proposal, we aim to use mice with a genetic predisposition to myopia or hyperopia to identify the genetic contributions to myopic eye growth, the influence of environmental factors on myopia susceptibility, and the components of the retinoscleral signaling cascade modulating refractive development. We outcrossed two inbred mouse strains, C57BL/6J and 129S1/SvlmJ, and generated second generation (F2) mice with hyperopic and myopic refractive errors, respectively. Taking advantage of the highly characterized mouse genome, we will use a genome-wide single nucleotide polymorphism (SNP) based strategy to identify regions of the genome that are associated with refractive errors through qualitative trait loci (QTL) mapping. Our preliminary analysis identified Dlgap2 as a promising candidate gene since it has been reported in human myopia genome-wide association studies. In the proposed experiments, we will test two QTL-identified candidate genes in targeted mouse mutants. We will also determine gene-environment interactions by investigating the response of the F2 mice to lens defocus myopia and different ambient light conditions. The genetic loci associated with the myopic phenotype in F2 mice will be compared to loci associated with lens-induced myopia. Lastly, we will use the F2 mice to investigate if dopamine- and/or hypoxia-associated signaling are necessary for myopic eye growth. Our proposed strategies will significantly expand our understanding of the polygenetic networks underlying myopia, increase our knowledge of the retinoscleral signaling needed for myopic eye growth and thus, form the basis for developing novel and more effective treatments for myopia.