Models for Vision Research

视觉研究模型

• 批准号: 7887712
• 负责人: Patsy M Nishina
• 金额: $ 99.38万
• 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/7887712
• 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; Hereditary Disease; Heritability; Histology; Human; Human Genetics; Impairment; In Situ; Induced Mutation; Infection; Information Distribution; Knowledge; Laboratories; 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; Public Health; Research; Resources; Retinal Diseases; Screening procedure; Study models; System; Testing; 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; public health relevance; sperm cell; therapeutic target; tool

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Virtually all non-traumatic and non-infectious ocular diseases in humans are genetic in origin or have a strong genetic component; genetic disorders account for more than 95% of common eye diseases. Identification of disease causing genes and animal models to study the disease progression and pathological consequences of mutations is extremely important. Many eye diseases in humans, if identified early enough, may be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights to new treatment regimens and the models can then be used to test those therapeutics. Finally, knowledge of the disease causing genes and the pathways in which they function may lead to an understanding that is critical in defining therapeutic targets for prevention of vision impairment and loss.

描述（由申请人提供）：全球约有5000万人盲目，约有1.5亿人受到明显的视力障碍。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。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20个突变线的分子基础，从中获得了许多独特的见解。在此应用中，我们计划完成剩余的40条线（AIM 1）的分子和表型表征，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，我们建议使用敏化的化学诱变筛选，以揭示Crumbs1途径重要的途径（AIM 2）。尽管有许多策略可用于识别主要基因/突变的相互作用因子，但化学诱导的突变的优势是，它们将允许对与Crumbs1相互作用的广泛基因的公正鉴定。这些基因可能解释了与Crumbs1中突变有关的大量疾病。它还将允许识别与Crumbs1的细胞外结构域相互作用的因素，Crumbs1（这是一种因当前可用方法而棘手的努力。在本应用中，我们将通过间接眼镜检查筛选约10,000个诱变的G3 Crumbs1rd8/rd8小鼠，以识别出发生变化的Crumbs1drd8底面表型的突变体。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，我们将研究新鉴定的基因/突变对Crumbs1途径的影响。该提案的成功结论不仅将产生良好的眼部模型，而且有可能识别进入Crumbs1途径的入口点以及在眼睛生物学中很重要的其他分子，并为我们提供了建立和测试有关正常眼功能和疾病病理学的假设的机会。 公共卫生相关性：实际上，人类中的所有非创伤和非感染性眼疾病都是遗传的，或具有强大的遗传成分；遗传疾病占常见眼病的95％以上。鉴定导致基因和动物模型研究突变的疾病进展和病理后果的疾病非常重要。人类的许多眼疾病（如果足够及早发现）可以治疗以减轻疾病过程。如果目前没有治疗，知道该疾病的分子基础可能会为新治疗方案提供见解，然后可以使用模型来测试这些治疗剂。最后，对导致基因的疾病的了解及其功能的途径可能会导致一种理解，这对于定义预防视力障碍和损失的治疗靶点至关重要。