Genetics of refractive error development in the mouse model

小鼠模型屈光不正发展的遗传学

• 批准号: 8754878
• 负责人: ANDREI V. TKATCHENKO
• 金额: $ 42.09万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754878
• 关键词: Address; Adult; Affect; Alleles; Animal Model; Asia; Blindness; Candidate Disease Gene; Cataract; Chickens; Contact Lenses; Control Locus; Data; Development; Disease; Ensure; Environment; Environmental Risk Factor; Epidemic; Epidemiology; Eye; Eye Development; Failure; Feedback; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Glass; Glaucoma; Goals; Growth; Haplotypes; Human; Human Gene Mapping; Hyperopia; Hypertension; Laboratories; Laboratory mice; Lead; Length; Mammals; Maps; Monkeys; Mouse Strains; Mus; Myocardial Infarction; Myopia; Ocular Pathology; Operative Surgical Procedures; Optics; Population; Prevalence; Process; Property; Proteins; Quantitative Trait Loci; RNA Sequences; Refractive Errors; Retina; Retinal Detachment; Risk; Risk Factors; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Stroke; System; Techniques; Testing; Tissues; Tupaiidae; United States; Validation; Variant; Vision; Visual; Work; base; cost; disorder of macula of retina; emmetropization; mouse model; novel; novel therapeutic intervention; prevent; public health relevance; trait

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.

描述（由申请人提供）：屈光眼发育是一个紧密协调的过程，其中视觉输入在称为“正视化”的过程中调节眼睛的生长。正视化过程由视网膜中的视觉驱动反馈回路和其他眼组织中的下游信号级联调节，通常导致眼睛的正确焦距和锐利视觉。正视化的失败导致屈光不正的发展（即，远视或近视）。在过去的30年里，美国人口中近视的患病率从25%增加到44%，在亚洲达到了流行病的比例;然而，人们对屈光眼发育的基因以及它们如何相互作用以及与环境相互作用来调节屈光眼发育知之甚少。发现屈光不正发展背后的遗传因素的努力由于难以识别人类中具有大环境贡献（例如常见近视）的疾病背后的染色体基因座而变得复杂。在传统的屈光眼发育动物模型（如猴、树和鸡）中，调节屈光眼发育的候选基因的验证和表征也存在问题，因为它们的基因组信息有限，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包括人类在内的其他哺乳动物基本相似。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，我们提出的数据，现有的遗传变异的实验室小鼠调节屈光眼的发展，产生小鼠品系与自然发生的远视，近视和正视。这些小鼠品系，结合我们实验室开发的近视小鼠模型，完善的小鼠QTL定位和基因靶向技术，代表了一个新的强大的平台，利用系统遗传学方法研究屈光眼发育的遗传机制。我们的中心假设是，小鼠屈光眼的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，以指导屈光眼的发育，并确定导致屈光不正发展的遗传因素。本申请的目的是使用系统遗传学方法鉴定小鼠模型中屈光眼发育的染色体基因座、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眼发育相关的染色体基因座，确定小鼠屈光眼发育相关的遗传网络中的菌株特异性差异，并确定和优先考虑小鼠屈光眼发育相关的候选基因。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，全面概述屈光眼发育的遗传网络，并确定导致屈光不正发展的基因。这些研究将增强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理学手段提供实验框架。