Genetics of refractive error development

描述（由申请人提供）：屈光眼发育是一个紧密协调的过程，通过视觉输入调节眼睛的生长，这一过程被称为“正视化”。正视化过程是由视网膜中的视觉驱动反馈回路和其他眼部组织中的下游信号级联调节的，通常导致眼睛的正确焦距和锐利视力。近视不完全会导致屈光不正（即远视或近视）的发生。在过去的30年里，美国人口的近视患病率从25%上升到44%，在亚洲达到了流行病的程度；然而，人们对屈光眼发展的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眼的发展知之甚少。揭示屈光不正发生的遗传因素的努力由于难以确定与环境有很大关系的人类疾病（如普通近视）的染色体位点而变得复杂。在屈光眼发育的传统动物模型（如猴子、树鼩和鸡）中，调节屈光眼发育的候选基因的验证和表征也存在问题，因为关于它们基因组的信息有限，而且缺乏既定的靶向基因组操作技术。我们最近证明，小鼠屈光眼的发育与其他哺乳动物（包括人类）的基本相似。我们还开发了一种近视小鼠模型，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眼的发育，产生具有自然发生的远视、近视和远视的小鼠品系。这些小鼠品系，结合我们实验室开发的小鼠近视模型，完善的小鼠QTL定位和基因靶向技术，为使用系统遗传学方法研究屈光眼发育的遗传机制提供了一个新的强大平台。我们的中心假设是，小鼠的屈光眼发育是由多种相互作用基因的菌株特异性等位基因调节的。我们的长期目标是了解遗传和环境因素如何相互作用以指导屈光眼的发展，并确定导致屈光不正发展的遗传因素。本应用程序的目的是利用系统遗传学方法在小鼠模型中识别屈光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发育的染色体位点，确定小鼠屈光性眼发育的菌株特异性遗传网络差异，并确定小鼠屈光性眼发育的候选基因并进行优先排序。本研究将利用系统遗传学的力量和一种新的近视小鼠模型，全面概述屈光眼发展的遗传网络，并确定屈光不正发展的基因。这些研究将增强我们对屈光不正发展的信号通路的理解，并将为开发治疗和预防近视的药物手段提供实验框架。

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.