Current research indicates that image blur or defocus alters eye growth and refraction and that the retina in large part governs these processes. However, a comprehensive understanding of the retinal signaling that accounts either for emmetropization (i.e., normal refraction) or for refractive errors has remained elusive, and clinically acceptable therapies that either prevent myopia onset or meaningfully slow its progression are unavailable. Despite major contributions to other fields, available molecular applications have not yet helped achieve a comprehensive mechanistic framework to understand the regulation of post-natal eye growth and refractive development. We hypothesize that visual stimuli altering eye growth induce transcriptome level changes in the retina and that these molecular signatures can identify important retinal mediators of refractive development. Our novel and far-reaching Preliminary Studies, defining retinal gene expression in form-deprivation myopia of chick, support this hypothesis. We propose transcriptome profiling of three established eye growth models in chick (concave spectacle lens, convex spectacle lens or goggle wear) and follow-up pharmacological and biochemical studies to establish potential roles in refractive development of the products of differentially regulated genes. Combining an interdisciplinary investigator team and core facilities at the University of Pennsylvania, we propose the following four inter-related Specific Aims: 1) identify differentially expressed retinal genes in lens-induced alterations of eye growth;2) profile differential gene expression by retinal pigment epithelium (RPE) in visually altered eye growth;3) establish the spatial distribution of differentially expressed retinal genes;and 4) characterize roles of the products of selected genes in eye growth regulation. We believe that our plan for transcriptome profiling and the related pharmacology will identify and characterize the molecular signaling by which the retina governs post-natal eye growth and refractive development. We anticipate that this work will generate novel and useful hypotheses that can be applied not only in the laboratory but also to the clinical study of refractive errors in children. We hope ultimately to stimulate the development of much needed, effective therapies to arrest myopia in children.
Despite the major public health impact, the etiologies of refractive errors generally and myopia in particular are poorly understood. We propose an innovative approach of evaluating altered gene expression in eyes of chicks developing refractive errors. Given past successes in applying findings in chick to human refractive development, we are optimistic that the proposed research will lead to novel ideas that can be used to understand and hopefully to treat the development of refractive errors in children.
| Pardue, Machelle T; Stone, Richard A; Iuvone, P Michael (2013) Investigating mechanisms of myopia in mice. Exp Eye Res 114:96-105 |
| Guggenheim, Jeremy A; McMahon, George; Northstone, Kate et al. (2013) Birth order and myopia. Ophthalmic Epidemiol 20:375-84 |
| Stone, Richard A; Pardue, Machelle T; Iuvone, P Michael et al. (2013) Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms. Exp Eye Res 114:35-47 |
| Stone, Richard A; McGlinn, Alice M; Baldwin, Donald A et al. (2011) Image defocus and altered retinal gene expression in chick: clues to the pathogenesis of ametropia. Invest Ophthalmol Vis Sci 52:5765-77 |
| Stone, Richard A; Khurana, Tejvir S (2010) Gene profiling in experimental models of eye growth: clues to myopia pathogenesis. Vision Res 50:2322-33 |
