Retinal circadian rhythms and refractive development

描述（由申请人提供）：屈光不正是光学散焦导致视力损害的主要原因，也是视网膜疾病以及青光眼和白内障的风险因素。 尽管对公共卫生有影响，但对屈光不正的病因了解甚少;并且不存在临床上可接受的使儿童屈光发育正常化的疗法。 图像质量调节屈光发育，视网膜在很大程度上控制着这一过程。 在最近完成的鸡眼睛生长模型中视网膜/（视网膜色素上皮）的基因表达谱分析中，我们确定了一个有趣的与屈光不正相关的视网膜基因网络：涉及内在视网膜时钟和昼夜节律的基因。 经过广泛研究，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），并且它通过涉及时钟基因及其蛋白质产物的相互连接的反馈回路来实现昼夜节律定时。 光是调节生物钟时间的主要环境输入。 许多报告还将照明（或假定的照明替代物）与实验室动物和儿童的屈光发育障碍相关联。 我们提出了创新的假设，即完整的内在视网膜昼夜节律是控制屈光发展的机制的基础，屈光不正可能来自昼夜节律控制的中断。 结合宾夕法尼亚大学和埃默里大学的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屈光不正的共同调节。 发展; 2）鉴定昼夜节律钟、褪黑激素受体和内在光敏神经节细胞（ipRGC）在屈光发育和眼睛生长中的作用;和3）建立昼夜节律基因和眼睛长度节律与已知调节屈光发育的药理学条件的相互作用。 我们的方法为建立一个长期寻求的框架，以了解屈光发展的生物学机制，并了解环境因素如何在分子水平上影响这一过程提供了很大的希望。 我们预计，这项工作将产生新的和有用的假设，不仅可以应用于实验室，但也在儿童屈光不正的研究。

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.