The reasons behind the development of myopia and its increasing incidence, particularly among educated people, remain obscure. The finding that animals can be made myopic or hyperopic by spectacle lenses that shift the plane of focus to behind the retina (hyperopic defocus) or in front of it (myopic defocus) demonstrates that refractive development is under homeostatic control. Because the eye can modulate its growth even if the optic nerve is severed, and because retinal defocus that is restricted to one area only affects the eye growth underlying that restricted area, it follows that the retina is able to detec the sign of the defocus and control the eye's growth. However, despite two centuries of study, prophylactic treatments against childhood myopia are limited to atropine drops, contact lenses that reshape the cornea, or stabilizing treatments for the sclera, all of which have potential side effects and limited efficacy. Work in our three labs (Nickla, Stone and Iuvone) has linked the development of ametropias to alterations in ocular circadian rhythms: eyes show shifts in phase and changes in amplitude of the rhythms in eye growth (axial length) and choroidal thickness that depend on the visual stimulus and are linked to changes in ocular growth. This proposal will constitute an interdisciplinary team approach that will apply the collaborators' expertise in applying catecholamine biochemistry and molecular biology to the mechanisms underlying refractive development. How the visual environment affects the growth of the eye and influences refractive error in humans continues to generate much interest, including contemporary studies relating time spent outdoors to the inhibition of myopia in school children, and studies on the deleterious impact of artificial nighttime lighting on human health. Our preliminary findings show that the chick eye's growth responses to exposures to brief visual stimuli such as defocus are dependent on the time of day of exposure, and that the rhythms in eye length and choroid thickness are altered in different ways. This application will address the questions of how variables in visual input affect retinal dopamine biochemistry, the rhythms in retinal clock- and circadian-related genes, and how these changes in retinal rhythms relate to the rhythms in eye length and choroid thickness. We will also look at how time-of-day of administration influences the effectiveness of 2 drugs that inhibit myopia in animal models, and one of which is used clinically (atropine), depend on time of day, and how their efficacy relates to the underlying retinal rhythms in dopamine and circadian clock genes. We will address these questions in chicks, a species with rapid and well-characterized compensatory responses to visual manipulations, and retinal/visual similarities to humans. We expect that this work will generate novel and useful hypotheses that can be applied both in the laboratory and can be extended to the study of refractive errors in children.
Myopia is reaching epidemic proportions in Asia and pathological myopia is a leading cause of blindness. Understanding how attributes of the visual environment influence the signal cascade between retina and sclera to produce myopia is crucial to developing therapies that will ameliorate it. We hypothesize that altered ocular circadian rhythms driven by the retinal clock play a role in the development of myopia. Understanding the molecular basis of these will stimulate the identification of much-needed, effective approaches to normalize refractive development in children.
