GENERATION OF MODELS FOR USHER SYNDROME

引子综合症模型的生成

• 批准号: 6460471
• 负责人: William J Kimberling
• 金额: $ 14.14万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460471
• 关键词: Macaca; Usher syndrome; animal genetic material tag; autosomal recessive trait; blindness; disease /disorder model; gene frequency; gene mutation; genetic screening; genotype; in vitro fertilization; model design /development; phenotype; polymerase chain reaction; retinitis pigmentosa; sensorineural hearing loss

DESCRIPTION: (Applicant's Abstract) Usher syndrome is an autosomal recessive disorder characterized by progressive retinitis pigmentosa (RP) and moderate to profound sensorineural hearing loss. It is the leading cause of combined deafness and blindness in the industrialized world, accounting for over half of the 20,000 deaf and blind people in the United States, and an additional 15,000-20,000 people with less severe hearing and vision loss. Mutations in the USH2A gene account for over half of Usher syndrome cases and approximately 10% of autosomal recessive RP, which affects approximately 67,000 people in the United States. Because gene functional differences lead to significant disparities in human vs. rodent retina function, mice and rats are incomplete models for RP. The expected outcome of this project, a macaque model for Usher syndrome, will be the foundation for important new clinical and basic studies. Our hypothesis, based on the carrier rate for the average recessive gene of 1/100 in humans, is that generating a model for a recessive human disease by screening outbred primates will be easier than by targeted deletion of the gene. Because mutations in the USH2A gene are the most common genetic cause of RP, we have chosen this gene for our initial screen. We will test our hypothesis in a stepwise fashion by accomplishing the following specific aims. 1) Screen a large population of macaques for mutations in the USH2A gene. Screening will be prioritized and putative mutation function will be evaluated based on our experience with human mutations. 2) Test the Putative USH2A Homozygotes for Phenotypic Relevance to Human Usher Ila.. Once putative pathologic mutations are found, mating or in vitro fertilization at Regional Primate Centers will be arranged to produce homozygous offspring, and proposals will be submitted to study the phenotype and establish USH2A macaque colonies. 3) Generate macaque models for additional Usher syndrome genes. As the emphasis in human disease research shifts to trials of prostheses and treatments, anatomical and physiological similarities between primates and humans have increased their importance as models. Responses to therapies will be similar in macaques and humans, increasing the relevance of clinical studies. Basic research on retinal degeneration in the macaque model will provide insights into pathologic mechanisms leading to retinitis pigmentosa, which will be the basis for designing and testing new treatments that could reduce or prevent inherited blindness.

描述：（申请人的摘要）Usher综合征是一种常染色体隐性疾病 深刻的感官听力损失。这是结合的主要原因 工业化世界的耳聋和失明，占一半以上 美国的20,000名聋人和盲人，还有一个 15,000-20,000人的听力和视力丧失较少。突变 USH2A基因占USHER综合征病例的一半以上，约为10％ 常染色体隐性RP，影响大约67,000人 美国。因为基因功能差异导致显着 人与啮齿动物视网膜功能，小鼠和大鼠的差异不完整 RP的型号。该项目的预期结果，是Usher的猕猴模型 综合征将成为重要的新临床和基础研究的基础。 我们的假设是基于平均隐性基因的载体率 1/100在人类中，是通过 筛选示意灵长类动物比通过针对性的删除更容易 基因。因为USH2A基因中的突变是最常见的遗传原因 RP，我们为初始屏幕选择了这个基因。我们将测试我们的 通过实现以下特定目的，以逐步的方式进行假设。 1）筛选了USH2A基因突变的大量猕猴。 将优先考虑筛选，并评估推定的突变功能 根据我们在人类突变的经验。 2）测试假定的USH2A 与人类Usher Ila的表型相关性的纯合子。 在区域发现，交配或体外受精的病理突变 灵长类动物中心将安排生产纯合后代和提案 将提交以研究表型并建立USH2A猕猴菌落。 3）生成猕猴模型，以实现其他usher综合征基因。作为重点 在人类疾病中，研究转向了假体和治疗的试验， 灵长类动物和人类之间的解剖学和生理相似性 提高了它们作为模型的重要性。对疗法的反应在 猕猴和人类增加了临床研究的相关性。基本的 猕猴模型中视网膜变性的研究将提供见解 进入导致色素性视网膜炎的病理机制，这将是 设计和测试可以减少或预防的新疗法的基础 继承的失明。