Genetics of refractive error development

描述(申请人提供)：屈光性眼睛发育是一个紧密协调的过程，在这个过程中，视觉输入调节眼睛的生长，这个过程被称为正视化。正视化过程由视网膜的视觉驱动反馈环和其他眼组织的下游信号级联调节，通常导致正确的眼睛焦距和敏锐的视力。正视化失败会导致屈光不正(即远视或近视)。在过去的30年里，近视在美国人口中的患病率从25%上升到44%，并在亚洲达到了流行的比例；然而，人们对屈光性眼睛发育的基础基因以及它们如何相互作用以及如何与环境相互作用来调节屈光性眼睛发育知之甚少。在人类中，由于对环境有较大影响的疾病(如常见的近视)潜在的染色体位点的识别困难，揭示屈光不正发生的遗传因素的努力变得复杂。在传统的屈光眼发育动物模型(如猴子、树鼠和鸡)中，对调节屈光眼发育的候选基因的验证和表征也是有问题的，因为关于它们基因组的信息有限，并且缺乏既定的定向基因组操作技术。我们最近已经证明，小鼠屈光不正的眼睛发育从根本上类似于包括人类在内的其他哺乳动物。我们还开发了一种近视的小鼠模型，它具有人类近视的所有特征。在这里，我们提供的数据表明，实验室小鼠现有的遗传变异调节屈光不正的眼睛发育，产生自然发生的远视、近视和正视的小鼠品系。这些小鼠品系与我们实验室建立的近视小鼠模型、成熟的小鼠QTL定位和基因打靶技术相结合，为利用系统遗传学方法研究屈光不正眼发育的遗传机制提供了一个新的强大的平台。我们的中心假设是，小鼠屈光不正的眼睛发育是由多个相互作用的基因的菌株特异性等位基因调控的。我们的长期目标是了解遗传和环境因素如何相互作用来指导屈光不正的眼睛发育，并确定导致屈光不正发展的遗传因素。这项应用的目的是利用系统遗传学方法在小鼠模型中识别导致屈光不正眼发育的染色体位点、基因和遗传网络。为了实现我们的目标，我们将绘制小鼠屈光性眼睛发育的染色体基因座图，识别小鼠屈光性眼睛发育的特定品系差异遗传网络中的特定菌株差异，并确定和优先选择可能导致小鼠屈光性眼睛发育的候选基因。这项拟议的研究将利用系统遗传学的力量和一种新的近视小鼠模型，全面概述屈光不正眼睛发育的遗传网络，并确定导致屈光不正发展的基因。这些研究将加深我们对屈光不正发生的信号通路的理解，并将为开发治疗和预防近视的药物方法提供一个实验框架。

DESCRIPTION (provided by applicant): Refractive eye development is a tightly coordinated process whereby visual input regulates growth of the eye in a process called "emmetropization". The emmetropization process is regulated by a vision-driven feedback loop in the retina and downstream signaling cascades in other ocular tissues, normally resulting in correct focal length of the eye and sharp vision. Failure of emmetropization leads to the development of refractive errors (i.e., farsightedness or nearsightedness). The prevalence of nearsightedness (myopia) in the U.S. population has increased from 25% to 44% over the last 30 years and reached epidemic proportions in Asia; however, very little is known about the genes underlying refractive eye development and how they interact with each other and with the environment to regulate refractive eye development. The efforts to uncover genetic factors underlying refractive error development are complicated by the difficulty with identification of chromosomal loci underlying diseases with large environmental contributions (such as common myopia) in humans. Validation and characterization of candidate genes regulating refractive eye development in traditional animal models of refractive eye development (such as monkeys, tree shrews and chickens) is also problematic because of limited information about their genomes and the lack of established techniques for targeted genome manipulation. We have recently demonstrated that mouse refractive eye development is fundamentally similar to that in other mammals, including humans. We have also developed a mouse model of myopia, which has all the features of human myopia. Here we present data that existing genetic variation in the laboratory mouse modulates refractive eye development yielding mouse strains with naturally occurring hyperopia, myopia and emmetropia. These mouse strains, in combination with the mouse model of myopia developed in our laboratory, well-established mouse QTL mapping and gene-targeting techniques, represent a novel powerful platform for studies of genetic mechanisms of refractive eye development using systems genetics approaches. Our central hypothesis is that refractive eye development in mice is regulated by strain-specific alleles of multiple interacting genes. Our long-term goal is to understand how genetic and environmental factors interact to guide refractive eye development and identify genetic factors responsible for the development of refractive errors. The objective of this application is to identify chromosomal loci, genes, and genetic networks underlying refractive eye development in the mouse model using systems genetics approaches. To achieve our objective, we will map chromosomal loci underlying refractive eye development in mice, identify strain-specific differences in genetic networks underlying strain-specific differences in refractive eye development in mice, and identify and prioritize candidate genes underlying refractive eye development in mice. The proposed studies will use the power of systems genetics and a new mouse model of myopia to provide the comprehensive overview of the genetic networks underlying refractive eye development and to identify genes responsible for the development of refractive errors. These studies will enhance our understanding of the signaling pathways underlying development of refractive errors, and will provide an experimental framework for the development of pharmacological means to treat and prevent myopia.