Models for Vision Research

视觉研究模型

基本信息

批准号：
7616705
负责人：
Patsy M Nishina
金额：
$ 83.23万
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/7616705
关键词：
Age Age-Months Anatomy Animal Model Anterior Assisted Reproductive Technology Biological Models Biology Breeding Candidate Disease Gene Chemicals Chromosome Mapping 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 Laboratories Location Maps Meiosis Methods Modeling Molecular Molecular Profiling Mus Mutagenesis Mutate Mutation Nature Neurosciences Online Mendelian Inheritance In Man Ophthalmoscopy Pathology Pathway interactions Physiological Processes Physiology Process Recombinants Research Retina Retinal Retinal Diseases Screening procedure Spottings Study models System Techniques Testing Time Tissues Transcript Trauma Vision Vision research age related aged base blind cost effective disease phenotype gain of function genetic manipulation genome database human disease information gathering loss of function mouse genome mouse model mutant novel positional cloning programs reproductive sperm cell trait web site

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）：全球约有5000万人是盲人，大约1.5亿人的视力受到了严重损害。除了创伤和感染外，大多数人眼疾病本质上都是遗传性的。引起视网膜疾病的人类基因座的数量比可用的相关动物模型的数量大约9倍，这表明在研究人类已知发生的疾病模型中存在较大的差距。具有良好发达遗传学的小鼠，与人类生理和解剖结构的相似性以及遗传操纵的可及性是一个广泛接受且有用的模型系统。小鼠模型已用于为人类疾病提供候选基因，在整个发育和疾病进展过程中进行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解剖生物学相关途径的理想平台。尽管有许多策略可生成小鼠模型，但化学诱变是产生眼部疾病的小鼠的最有效方法之一。 ENU诱导的突变允许公正地鉴定出多种基因对眼生生物学的影响不同。在本应用中，我们将通过间接眼镜检查，狭缝灯生物显微镜和电子测术筛选约10,000名年龄G3小鼠。我们的目标是确定50个模型，具有可遗传的前部或后段异常。重要的是，其中，我们将使用标准和辅助生殖方法的组合，将大约30个具有视网膜异常的模型绘制或互补测试，并继续进行定位候选测试或克隆10-20。具有可证明的可遗传突变的小鼠将通过本赠款中建立的网站以及通过研究殖民地生成的小鼠发达的JAX分配系统提供给视觉研究社区。将为所有两个适当年龄的模型提供前段或底面的光照，电视图和组织学，以确定该疾病是固定的还是进行的。在确定基本分子基础的视网膜模型中，将通过实时PCR建立发育表达曲线，并在表达最高的年龄进行现场分析。该提案的成功结论不仅将产生良好的眼部模型，而且可能会识别出对眼睛生物学重要的新途径的入口点，并为我们提供了建立和检验有关正常眼功能和疾病病理学的假设的机会。