Genetics of refractive error development

屈光不正发展的遗传学

基本信息

批准号：
8929252
负责人：
ANDREI V. TKATCHENKO
金额：
$ 39.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8929252
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 Genetic study Genome Glass Glaucoma Goals Growth Haplotypes Health 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 genetic approach mouse model novel novel therapeutic intervention prevent trait transcriptome sequencing

项目摘要

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）：折射眼的发育是一个紧密协调的过程，在称为“弹性化”过程中，视觉输入调节眼睛的生长。弹性过程受视网膜和其他眼组织的下游信号级联反馈回路调节，通常导致眼睛的正确焦距和敏锐的视力。弹性化的失败会导致折射率的发展（即远视或近视性）。在过去的30年中，美国人口的近视（近视）的患病率从25％增加到44％，并达到了亚洲的流行比例。但是，关于屈光眼发育的基因以及它们如何相互相互作用以及与环境调节折射眼发育的知之甚少。难以确定人类具有较大环境贡献（例如普通近视）的染色体基因座基因座基因座基因座基因座基因座基因座的难度，揭示折射误差发展的遗传因素的努力变得复杂。在传统的折射眼发育模型（例如猴子，树生和鸡）中调节屈光眼发育的候选基因的验证和表征，因为有关其基因组的信息有限，并且缺乏针对性基因组操纵的既定技术。我们最近证明，小鼠折射眼发育与包括人类在内的其他哺乳动物的根本相似。我们还开发了近视的老鼠模型，该模型具有人类近视的所有特征。在这里，我们提供的数据表明，实验室小鼠中现有的遗传变异调节折射眼发育，从而产生了自然发生的远视，近视和Emmetropia的小鼠菌株。这些小鼠菌株结合了实验室中开发的近视的小鼠模型，建立了良好的小鼠QTL映射和靶向基因靶向技术，代表了一个新型的强大平台，用于研究使用系统遗传学方法来研究折射眼发育的遗传机制。我们的中心假设是，小鼠的折射眼发育受到多个相互作用基因的菌株特异性等位基因的调节。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眼睛发育并确定导致屈光不正的发展的遗传因素。该应用的目的是使用系统遗传学方法来识别小鼠模型中折射眼发育的基础染色体基因座，基因和遗传网络。为了实现我们的目标，我们将绘制小鼠折射眼发育的染色体基因座，确定小鼠折射眼发育中菌株特异性差异的菌株特异性差异，并识别和确定小鼠折射眼发育的候选基因的优先级和优先级。拟议的研究将利用系统遗传学的力量和新的近视小鼠模型，以提供折射眼发育的遗传网络的全面概述，并确定负责屈光误差发展的基因。这些研究将增强我们对折射错误发展的信号通路的理解，并将为制定治疗和预防近视的药理手段提供实验框架。