Molecular Characterization of Chick Retina during Refractive Development

描述(申请人提供)：目前的研究表明，图像模糊或散焦会改变眼睛的生长和屈光状态，而视网膜在很大程度上控制着这些过程。然而，对导致正视化(即正常屈光不正)或屈光不正的视网膜信号的全面了解仍然是难以捉摸的，临床上可接受的预防近视发生或显著减缓其进展的治疗方法也是不可获得的。尽管对其他领域做出了重大贡献，但现有的分子应用尚未帮助实现全面的机制框架，以了解出生后眼睛生长和屈光发育的调节。我们假设，改变眼睛生长的视觉刺激会导致视网膜转录组水平的变化，这些分子特征可以识别视网膜屈光发育的重要介质。我们新颖而深远的初步研究定义了雏鸡形觉剥夺性近视的视网膜基因表达，支持这一假说。我们建议对三种已建立的鸡眼生长模型(凹面眼镜镜片、凸面眼镜镜片或护目镜佩戴)进行转录组分析，并进行后续的药理学和生化研究，以确定差异调控基因产物在屈光发育中的潜在作用。结合一个跨学科的研究团队和宾夕法尼亚大学的核心设施，我们提出了以下四个相互关联的具体目标：1)确定晶状体诱导的眼生长变化中差异表达的视网膜基因；2)视网膜色素上皮(RPE)在视觉变化的眼生长中的差异基因表达；3)建立差异表达视网膜基因的空间分布；以及4)表征所选基因产物在眼生长调节中的作用。我们相信，我们的转录组图谱计划和相关的药理学将识别和表征视网膜控制出生后眼睛生长和屈光发育的分子信号。我们预计这项工作将产生新的和有用的假说，不仅可以应用于实验室，也可以应用于儿童屈光不正的临床研究。我们希望最终刺激急需的有效疗法的发展，以遏制儿童近视。与公众健康相关：尽管对公众健康有重大影响，但屈光不正，尤其是近视的病因尚不清楚。我们提出了一种创新的方法来评估发生屈光不正的雏鸡眼睛中基因表达的变化。鉴于过去将鸡的研究结果应用于人类屈光发育的成功，我们乐观地认为，拟议的研究将带来新的想法，可以用来理解并有望治疗儿童屈光不正的发展。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.