GENERATION OF MODELS FOR GENETIC HEARING LOSS

遗传性听力损失模型的生成

• 批准号: 6488117
• 负责人: DANA Jo ORTEN
• 金额: $ 7.2万
• 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: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6488117
• 关键词: Macaca; animal breeding; animal colony; disease /disorder model; family genetics; gap junctions; gene frequency; gene mutation; genetic disorder; genetic models; genetic screening; hearing disorders; in vitro fertilization; mass screening; membrane channels; model design /development; phenotype

DESCRIPTION (provided by applicant): The ultimate objective of this proposal is to create macaque models for the most prevalent types of hearing loss. Mutations in the gene for connexin 26 (GJB2) are the most common cause of hearing loss (DFNB1) in American and European populations, accounting for about 10% of all childhood hearing loss. An animal model is not available to study connexin 26 function in the ear because the mouse knockout is embryonic lethal. The expected outcome of this project, a macaque connexin 26 hearing loss model, will provide a foundation for important new clinical and basic studies of the most common type of inherited hearing loss. Our hypothesis, based on the carrier rate for the average recessive gene of about 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 in mice. Because mutations in GJB2 gene are the most common genetic cause of hearing loss, we have chosen this gene for our initial screen. The sequence is conserved between human and macaque with 18 base changes and 4 amino acid changes observed. 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 GJB2 gene. Screening will be prioritized and putative mutation function will be evaluated based on our experience with human mutations. 2) Test the putative GJB2 homozygotes for phenotypic relevance. 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 GJB2 macaque colonies. 3) Generate macaque models for additional hearing loss genes. Anatomical and physiological similarities between primates and humans have increased the importance of primate models. Responses of macaques to therapies will be similar to humans, increasing relevance of clinical studies. Basic hearing loss research in the macaque model will provide insights into pathologic mechanisms leading to hearing loss in humans. Understanding disease processes will be the basis for designing and testing new treatments that could reduce or prevent human inherited hearing loss.

描述（由申请人提供）：该提案的最终目标是 为最常见的听力损失类型创建猕猴模型。突变 连接蛋白 26 (GJB2) 基因中的连接蛋白 26 (GJB2) 是听力损失的最常见原因 (DFNB1) 在美国和欧洲人群中，约占总人口的 10% 儿童时期听力损失。没有可用于研究连接蛋白 26 的动物模型 耳朵中的功能，因为小鼠基因敲除是胚胎致死的。预期的 该项目的成果，猕猴连接蛋白 26 听力损失模型，将提供 为最常见的重要新临床和基础研究奠定基础 遗传性听力损失的类型。我们的假设基于携带率 人类平均隐性基因约为1/100，生成模型 通过筛查远交灵长类动物来治疗隐性人类疾病将比 通过在小鼠体内有针对性地删除该基因。因为 GJB2 基因突变 听力损失最常见的遗传原因，我们选择这个基因作为我们的听力损失基因 初始屏幕。该序列在人类和猕猴之间是保守的，有 18 个碱基 观察到 4 个氨基酸变化。我们将检验我们的假设 通过实现以下具体目标逐步实现时尚。 1）屏幕大 猕猴群体中 GJB2 基因突变。筛选将是 优先和假定的突变函数将根据我们的评估 人类突变的经验。 2) 测试假定的 GJB2 纯合子 表型相关性。一旦发现假定的病理突变，交配或 将安排在区域灵长类动物中心进行体外受精，以生产 纯合子后代，并将提交提案来研究表型和 建立GJB2猕猴群。 3) 生成额外的猕猴模型 听力损失基因。灵长类动物之间的解剖学和生理学相似性 人类增加了灵长类动物模型的重要性。的回应 猕猴的治疗方法将与人类相似，从而增加了相关性 临床研究。猕猴模型的基础听力损失研究将提供 深入了解导致人类听力损失的病理机制。 了解疾病过程将成为设计和测试新产品的基础 可以减少或预防人类遗传性听力损失的治疗方法。