Models for Vision Research

视觉研究模型

基本信息

批准号：
7687175
负责人：
Patsy M Nishina
金额：
$ 18.52万
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/7687175
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）：全世界大约有 5000 万人失明，大约 1.5 亿人视力严重受损。除外伤和感染外，大多数人类眼部疾病本质上都是遗传性的。引起视网膜疾病的人类基因座数量大约是现有相关动物模型数量的 9 倍，这表明用于研究已知人类疾病的模型存在巨大差距。小鼠具有发达的遗传学、与人类生理学和解剖学的相似性以及易于进行基因操作，是一种被广泛接受和有用的模型系统。小鼠模型已被用来提供人类疾病的候选基因、用于整个发育和疾病进展研究的组织以及治疗测试系统。它们也是通过遗传手段识别和剖析生物学相关途径的理想平台。虽然有许多策略可用于生成小鼠模型，但化学诱变是生成患有眼病的小鼠的最有效方法之一。 ENU 诱导的突变可以公正地鉴定对眼生物学具有不同影响的多种基因。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图检查大约 10,000 只老年 G3 小鼠。我们的目标是识别 50 个具有可遗传的前段或后段异常的模型。重要的是，我们将绘制或补充测试大约 30 个视网膜异常模型，并结合标准和辅助生殖方法继续进行位置候选测试或克隆其中 10-20 个模型。具有已证实可遗传突变的小鼠将通过本次拨款建立的网站以及针对研究群体产生的小鼠的完善的 JAX 分配系统提供给视觉研究界。将为所有模型提供两个适当年龄的眼前段或眼底照片记录、视网膜电图和组织学，以确定疾病是静止的还是进展的。在确定了潜在分子基础的视网膜模型中，将通过实时PCR建立发育表达谱，并在表达最高的年龄进行眼睛的原位分析。该提案的成功完成不仅将产生特征良好的眼部模型，而且有可能确定眼生物学中重要的新途径的切入点，并使我们有机会建立和测试有关正常眼部功能和疾病病理学的假设。