Retinal circadian rhythms and refractive development

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DESCRIPTION (provided by applicant): Refractive errors are a major cause of visual impairment from optical defocus and are risk factors for retinal disorders, as well as for glaucoma and cataract. Despite the public health impact, the etiologies of refractive errors are poorly understood; and clinically acceptable therapies to normalize refractive development in children do not exist. Image quality modulates refractive development, and the retina largely governs this process. In recently completed gene expression profiling of the retina/(retinal pigment epithelium) in eye growth models in chick, we identified an intriguing retinal gene network associated with refractive error: genes involved in intrinsic retinal clock and circadian rhythms. Extensively studied, the retina has many intrinsic circadian rhythms (e.g., disc shedding, melatonin secretion), and it achieves circadian timing through interconnected feedback loops involving clock genes and their protein products. Light is the major environmental input regulating the timing of circadian clocks. Many reports also have associated lighting (or putative surrogates of lighting) with disordered refractive development both in laboratory animals and in children. We propose the innovative hypothesis that intact intrinsic retinal circadian rhythms are fundamental to the mechanism controlling refractive development and that refractive errors might arise from disruptions of circadian control. Combining experienced investigators at Penn and Emory, we shall address this hypothesis with three inter-related Specific Aims: 1) identify the co-regulation of circadian genes and refractive development; 2) identify the role(s) of circadian clocks, melatonin receptors, and intrinsically photosensitive ganglion cells (ipRGCs) in refractive development and eye growth; and 3) establish the interaction of circadian genes and eye length rhythms with pharmacologic conditions known to modulate refractive development. Our approach offers great promise for establishing a long-sought framework to understand the biological mechanisms of refractive development and to learn how environmental factors might influence the process at a molecular level. We anticipate that this work will generate novel and useful hypotheses that can be applied not only in the laboratory but also to the study of refractive errors in children.