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Models for Vision Research

视觉研究模型

基本信息

批准号：
7217859
负责人：
Patsy M Nishina
金额：
$ 78.53万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7217859
关键词：
Age Age-Months Anatomy Animal Model Anterior Assisted Reproductive Technology Biological Models Biology Breeding Candidate Disease Gene Chemical Models Chemicals Chromosome Mapping Class Communities DNA Data Development Disease Disease Progression Disease model Electroretinography Embryo Ensure Ethylnitrosourea Eye Eye diseases Family Fertilization in Vitro Fundus Future Genes Genetic Genetic Complementation Test Genomics Goals Grant Histology Home Page Human In Situ Induced Mutation Infection Information Distribution Internet Laboratories Localized Location Maps Meiosis Methods Modeling Molecular Molecular Profiling Mus Mutagenesis Mutate Mutation Nature Neurosciences Numbers Online Mendelian Inheritance In Man Ophthalmoscopy Pathology Pathway interactions Physiological Processes Physiology Polymerase Chain Reaction Process Purpose Recombinants Research Retina Retinal Retinal Diseases Screening procedure Site Spottings Standards of Weights and Measures Study models System Techniques Testing Time Tissues Transcript Trauma Vision Vision research Week age related aged base blind cost effective disease phenotype gain of function genetic manipulation genome database human disease information gathering loss of function mouse model mutant novel positional cloning programs reproductive sperm cell trait

项目摘要

DESCRIPTION (provided by applicant): Approximately 50 million people world-wide are blind and approximately 150 million are significantly vision impaired. Except for trauma and infections, the majority of human eye diseases are genetic in nature. The number of human loci causing retinal disease is approximately 9-fold greater than the number of available associated animal models, indicating a large gap in models for studying diseases that are known to occur in humans. The mouse with its well-developed genetics, similarity to human physiology and anatomy, and accessibility for genetic manipulation is a widely accepted and useful model system. Mouse models have been used to provide candidate genes for human diseases, tissues for study throughout development and disease progression, and test systems for therapies. They are also an ideal platform to identify and dissect biologically relevant pathways through genetic means. While there are many strategies available to generate mouse models, chemical mutagenesis is one of the most efficient methods to produce mice with eye diseases. ENU-induced mutations allow unbiased identification of a wide array of genes with different effects on ocular biology. In the present application, we will screen approximately 10,000 aged G3 mice by indirect ophthalmoscopy, slit lamp biomicroscopy, and electroretinography. Our goal is to identify 50 models with heritable anterior segment or posterior segment abnormalities. Importantly, of these, we will map or complementation test approximately 30 models with retinal abnormalities and go on to positionally candidate test or clone 10-20 of these using a combination of standard and assisted reproductive approaches. Mice with proven heritable mutations will be made available to the vision research community through a website established in this grant and through the well-developed JAX distribution system for mice generated from research colonies. Anterior segment or fundus photo-documentation, electroretinography and histology will be provided for all models at two appropriate ages to determine if the disease is stationary or progressive. In the retinal models where the underlying molecular basis is determined, a developmental expression profile will be established by real time PCR, and in situ analysis of the eye will be carried out at an age in which expression is highest. Successful conclusion of this proposal will not only generate well characterized ocular models, but will potentially identify entry points into new pathways that are important in eye biology and afford us the opportunity to build and test hypotheses about normal ocular function and disease pathology.

描述（由申请人提供）：全世界约有5000万人失明，约1.5亿人视力严重受损。除了外伤和感染外，大多数人类眼病都是遗传性的。导致视网膜疾病的人类基因座的数量大约是现有相关动物模型数量的9倍，表明用于研究已知发生在人类中的疾病的模型存在很大差距。小鼠具有良好的遗传学，与人类生理学和解剖学的相似性，以及遗传操作的可访问性，是一种被广泛接受和有用的模型系统。小鼠模型已被用于提供人类疾病的候选基因、用于整个发育和疾病进展的研究的组织以及用于治疗的测试系统。它们也是通过遗传手段识别和剖析生物相关途径的理想平台。虽然有许多策略可用于产生小鼠模型，但化学诱变是产生患有眼病的小鼠的最有效方法之一。ENU诱导的突变允许无偏见地鉴定对眼部生物学具有不同影响的广泛基因。在本申请中，我们将通过间接检眼镜检查、裂隙灯生物显微镜检查和视网膜电描记术筛选约10，000只老年G3小鼠。我们的目标是确定50个模型与遗传性眼前节或后节异常。重要的是，在这些模型中，我们将绘制或补充测试大约30个视网膜异常模型，并使用标准和辅助生殖方法的组合进行定位候选测试或克隆其中的10-20个。具有经证实的遗传突变的小鼠将通过在该赠款中建立的网站和通过用于研究群体产生的小鼠的发达的JAX分配系统提供给视觉研究社区。将提供两个适当年龄的所有模型的眼前节或眼底照片记录、视网膜电图和组织学，以确定疾病是静止的还是进行性的。在确定潜在分子基础的视网膜模型中，将通过真实的时间PCR建立发育表达谱，并在表达最高的年龄进行眼的原位分析。成功的结论，这一建议将不仅产生良好的表征眼部模型，但将有可能确定进入新的途径，是重要的眼睛生物学，并为我们提供了机会，建立和测试有关正常的眼睛功能和疾病病理的假设。