Retinal circadian rhythms and refractive development

描述（由申请人提供）：屈光不正是光学离焦导致视力损害的主要原因，也是视网膜疾病、青光眼和白内障的危险因素。尽管对公众健康有影响，但屈光不正的病因却知之甚少；临床上可接受的使儿童屈光发育正常化的治疗方法尚不存在。图像质量调节折射发展，而视网膜在很大程度上控制着这一过程。在最近完成的鸡眼生长模型视网膜色素上皮的基因表达谱中，我们发现了一个与屈光不正相关的有趣的视网膜基因网络：涉及内在视网膜时钟和昼夜节律的基因。广泛研究表明，视网膜具有许多内在的昼夜节律（例如，椎间盘脱落，褪黑激素分泌），它通过涉及时钟基因及其蛋白质产物的相互关联的反馈回路实现昼夜节律定时。光是调节生物钟时间的主要环境输入。许多报告还将照明（或假定的照明替代品）与实验动物和儿童的屈光发育障碍联系起来。我们提出了一个创新的假设，即完整的内在视网膜昼夜节律是控制屈光发育机制的基础，屈光不正可能是由于昼夜节律控制的中断而引起的。结合宾夕法尼亚大学和埃默里大学经验丰富的研究人员，我们将通过三个相互关联的具体目标来解决这一假设：1)确定昼夜节律基因和折射的共同调节

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.