Animal Models of Ocular Disease

 描述(申请人提供)：该项目的长期目标是建立一系列用于研究人类视觉系统障碍的非人类灵长类动物模型。目前，小鼠是这一领域使用的主要模型系统，这在很大程度上是因为我们有能力产生用于特定疾病研究的基因工程动物。然而，尽管老鼠和其他啮齿动物与人类相似，但它们并没有富含视锥的黄斑，这是对人类视觉最关键的区域。因此，一个与人类更接近的非人灵长类(NHP)模型系统将为疾病过程提供重要的新见解，并为开发和测试针对特定眼病的新疗法或预防措施提供更好的机会。我们对200只猕猴(猕猴)的初步测序结果表明，猕猴之间的遗传多样性远远大于人之间的遗传多样性。在猕猴中，我们发现许多个体携带已知的人类视网膜疾病基因的致病突变。因此，猕猴模型代表着一个黄金但目前尚未开发的创新研究机会。利用现有的基础设施来产生广泛的新的灵长类模型(具有信息突变的繁育系)是可行的，这些模型对于关于发病机制的研究和治疗的开发将是非常有价值的。为了证明这种方法的可行性并开始挖掘其潜力，我们建议：目标1.对1600只猕猴进行视网膜疾病基因的定向测序。目的2.建立猕猴眼部基因突变数据库。目的3.建立多种人类眼部疾病的猕猴模型。目标4.确定所产生的表型并开始测试猕猴模型的治疗

 DESCRIPTION (provided by applicant): The long-term goal of this project is to establish a series of nonhuman primate models for the investigation of human visual system disorders. Currently, the mouse is the predominant model system used in this field, largely due to our ability to generate genetically engineered animals for the study of specific diseases. However, despite their similarities with humans, mice and other rodents do not have a cone-rich macula, the region most critical for human vision. Therefore, a nonhuman primate (NHP) model system that more closely matches human will offer important new insights into disease processes and provide much improved opportunities for development and testing of novel treatments or preventions for specific eye diseases. Our initial sequencing results from ~200 rhesus macaques (Macaca mulatta) indicate that the genetic diversity among macaques is much greater than among people. Among the macaques, we found many individuals carrying pathogenic mutations in known human retinal disease genes. Therefore, the macaque model represents a golden but currently untapped opportunity for innovative research. It is feasible to leverage existing infrastructure to generate a wide range of novel primate models (breeding lines with informative mutations) that will be invaluable for research concerning pathogenesis and the development of treatments. To demonstrate the feasibility of this approach and begin exploiting its potential, we propose to: Aim 1. Perform targeted sequencing of retinal disease genes in 1,600 individual rhesus macaques. Aim 2. Establish a mutational database for macaque eye genes. Aim 3. Generate multiple macaque models of human eye diseases. Aim 4. Characterize the phenotypes produced and begin testing of treatments of macaque models