Models for Vision Research

视觉研究模型

• 批准号: 8266455
• 负责人: Patsy M Nishina
• 金额: $ 98.27万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266455
• 关键词: Accounting; Affect; Alleles; Anatomy; Animal Model; Attenuated; Award; Biological Models; Biology; Candidate Disease Gene; Chemicals; Clinical; Cloning; Communities; Controlled Environment; DNA; Databases; Defect; Development; Disease; Disease Outcome; Disease Progression; Electroretinography; Embryo; Ensure; Environmental Risk Factor; Ethylnitrosourea; Extracellular Domain; Eye; Eye diseases; Frequencies; Funding; Fundus; Future; Gene Mutation; Gene-Modified; Genes; Genetic; Genetic Heterogeneity; Genomics; Goals; Health; Hereditary Disease; Heritability; Histology; Human; Human Genetics; Impairment; In Situ; Induced Mutation; Infection; Information Distribution; Knowledge; Lead; Learning; Leber' s amaurosis; Location; Maps; Methodology; Methods; Microscopy; Modeling; Modification; Molecular; Molecular Profiling; Mus; Mutagenesis; Mutation; Nature; Ophthalmoscopy; Outcome; Pathology; Pathway interactions; Phenotype; Physiological; Physiological Processes; Physiology; Prevention; Process; Research; Resources; Retinal Diseases; Screening procedure; Study models; System; Testing; The Jackson Laboratory; Therapeutic; Tissues; Transcript; Trauma; Treatment Protocols; Vision; Vision research; base; blind; disease phenotype; gain of function; gene discovery; genetic manipulation; human disease; in vivo; insight; loss of function; mouse model; mutant; new technology; programs; sperm cell; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT Approximately 50 million people worldwide are blind and ~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 ~ 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. In the last funding cycle, we generated >60 models with ocular defects. We have identified the molecular basis of 20 of the mutant lines from which many unique insights were obtained. In this application, we plan to complete the molecular and phenotypic characterization of the 40 remaining lines (Aim 1) and make them available to the scientific research community. Extending our ongoing genetic studies, we propose to use a sensitized chemical mutagenesis screen to reveal pathways important in the Crumbs1 pathway (Aim 2). While there are many strategies available to identify interacting factors of primary genes/mutations, chemically induced mutations have the advantage that they will allow for the unbiased identification of a wide array of genes that interact with CRUMBS1. These genes may explain the plethora of diseases associated with mutations within Crumbs1. It will also allow for identification of factors that interact with the extracellular domain of CRUMBS1, an endeavor that has been intractable by the current available methods. In the present application, we will screen ~10,000 mutagenized G3 Crumbs1rd8/rd8 mice by indirect ophthalmoscopy to identify mutants that present with an altered Crumbs1drd8 fundus phenotype. The molecular bases of these factors will be identified and through the use of standard immunohistochemical methodologies in conjunction with the use of 4Pi microscopy, we will examine the effects of the newly identified genes/mutations on the CRUMBS1 pathway. Successful conclusion of this proposal will not only generate well characterized ocular models, but will potentially identify entry points into the CRUMBS1 pathways as well as other molecules that are important in eye biology and afford us the opportunity to build and test hypotheses about normal ocular function and disease pathology.

项目摘要/摘要 全球约有5000万人盲目，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。数量 引起视网膜疾病的人类基因座比可用的相关动物模型的数量大约9倍， 表明在研究人类中已知发生的疾病模型中存在很大的差距。鼠标及其 发达的遗传学，与人类生理学和解剖学的相似性以及遗传的可及性 操作是一个被广泛接受且有用的模型系统。鼠标模型已用于提供 人类疾病的候选基因，在整个发育和疾病进展过程中进行研究的组织以及 治疗系统的测试系统。它们也是识别和剖析生物学相关的理想平台 通过遗传手段的途径。 在最后一个融资周期中，我们生成了具有眼部缺陷的60个型号。我们已经确定了分子 在从中获得许多独特见解的20个突变线的基础。在此应用程序中，我们计划 完成40条线的分子和表型表征（AIM 1），并使它们 可用于科学研究界。 扩展我们正在进行的遗传研究，我们建议将敏化的化学诱变筛选到 揭示Crumbs1途径重要的途径（AIM 2）。虽然有许多策略可供 识别主要基因/突变的相互作用因子，化学诱导的突变具有一个优势 它们将允许对与Crumbs1相互作用的广泛基因的公正识别。这些 基因可以解释与Crumbs1中突变有关的大量疾病。它也将允许 鉴定与Crumbs1的细胞外结构域相互作用的因素，Crumbs1是一项努力 通过当前可用的方法可棘手。在本应用中，我们将筛选约10,000个诱变 G3 Crumbs1rd8/rd8小鼠通过间接眼镜检查，以识别出发生变化的Crumbs1drd8的突变体 眼底表型。将确定这些因素的分子碱基，并通过使用标准 免疫组织化学方法与4PI显微镜结合使用，我们将检查这些影响 Crumbs1途径上新鉴定的基因/突变。 该提案的成功结论不仅会产生良好的眼部模型，而且会产生 有可能识别进入Crumbs1途径的入口点以及其他重要的分子 眼睛生物学，使我们有机会建立和测试有关正常眼功能和的假设 疾病病理学。