A National NHP Embryo Resource of Human Genetic Disease Models

项目摘要 该项目的目标是开发 （NHP） 疾病 NHP 的 疾病 模型 不可治愈 的 两 女性 需要 在 的 在 已经 工作人员 发现 相关 前沿 目的： 公共， 到 培训 遗传 研究 NHP 疾病 保护和利用非人类灵长类动物的国家资源 人类遗传疾病的模型。许多实验室正在开发新的遗传疗法， 需要大型动物模型来评估安全性和有效性。与啮齿动物和其他动物相比， 人类疾病模型对于开发新药和其他方法更有价值 在人类身上得到了成功的应用近年来，研究人员建立了多种人类遗传性自发NHP模型， 美国国家灵长类动物研究中心（NPRCs）这些NHP基因 提供了非凡的机会，以显着推进研究和治疗目前 疾病，包括最先进的精准医疗方法的临床前测试。 约束影响这些NHP模型的有效繁殖和可用性。首先，由于大多数 所鉴定的疾病显示常染色体隐性遗传，平均只有1/4的后代由 等位基因携带者是纯合子和受影响的。生育年龄的雄性数量往往不足， 等位基因携带者及时产生足够的受试者。其次，对于超稀有等位基因，育种可能 使用位于多个NPRC设施的有限数量的等位基因携带者。第三，收入增加 疫苗研究对NHP的需求严重威胁着模型等位基因携带者的长期可用性。 为了克服这些挑战，我们的目标是建立国家NHP模型胚胎资源（NNMER）。 俄勒冈州NPRC（ONPRC）将优化和实施最先进的NHP配子收集协议， 受影响胚胎和携带者胚胎的体外受精、囊胚基因分型和胚胎冷冻保存 特征疾病模型。此外，ONPRC将为兽医提供培训和支持， 在五个合作的NPRCs，以确保有效地收集配子从现有的和新的 位于每个中心的疾病模型载体。长期目标是提供生物医学- 国家资源，可供任何对NHP遗传模型感兴趣的研究人员使用，这将使 临床前研究和治疗开发。为了实现这些目标，我们提出以下建议 (1)建立全国NHP遗传病模型配子、胚胎和成纤维细胞资源， 可搜索的工具，用于长期保存和访问有价值的NHP疾病模型; 支持全国范围内的NHP配子收集和基因型模型胚胎的产生， （3）促进NHP的广泛使用 疾病胚胎资源，通过系统的推广工作，旨在达到临床医生和 全国各地的调查员。这种高度新颖的资源将提供强大的，基因平行， 研究人员和临床医生推进研究，以了解人类遗传机制的模型 发病机制和评估新的治疗策略。 几 不 到 L G （二）

PROJECT SUMMARY The goal of this project is to develop (NHP) diseases NHP that diseases models uncurable of two female require in The in already staff discovered relevant cutting-edge aims: public, To training genetic research NHP disease a national resource for the preservation and use of non-human primate models of human genetic diseases. Numerous laboratories are developing novel therapies for genetic that require large animal models to assess safety and efficacy. Compared to rodents and other animals, models of human diseases have been far more valuable for developing new drugs and other approaches go on to be successfully used in humans. Recently, a variety of spontaneous NHP models of human genetic have been identified at the U.S. National Primate Research Centers (NPRCs). These NHP genetic present extraordinary opportunities to significantly advance the study and treatment of currently diseases, including the pre-clinical testing of state-of-the-art precision medicine approaches. constraints impact the efficient breeding and availability of these NHP models. First, since most the identified diseases display autosomal recessive i nheritance, on average only 1 in 4 offspring produced by allele carriers is homozygous and affected. There are often insufficient numbers of breeding age male and allele carriers to produce sufficient subjects in a timely way. Second, for ultra-rare alleles, breeding may the use of a l imited number of allele carriers located at multiple NPRC facilities. Third, r ecen increases demand for NHPs for vaccine research severely threatens the long-term availability of model allele carriers. overcome these challenges, we aim to generate a National NHP Model Embryo Resource (NNMER). Oregon NPRC (ONPRC) will optimize and implement state-of-the-art protocols for NHP gamete collection, vitro f ertilization, blastocyst genotyping and embryo cryopreservation of affected and carrier embryos of characterized disease models. Moreover, the ONPRC wil provide training and support for veterinary at five partnering NPRCs to ensure t he efficient collection of gametes from both current and newly disease model carriers located at each center. The long-term goal is to provide a biomedically- national resource, accessible to any investigator interested in NHP genetic models, that will enable preclinical research and therapeutic development. To achieve these oals, we propose the following (1) To establish a national NHP genetic disease model gamete, embryo and fibroblast resource and a searchable tool for the long-term preservation of and accessibility to valuable NHP disease models; support nationwide collection of NHP gametes and the generation of genotyped model embryos by providing in state-of-the-art assisted reproductive technologies; and (3) To promote widespread use of the NHP disease embryo resource through systematic outreach efforts aimed at reaching both clinicians and investigators nationwide. This proposed highly novel resource will provide powerful, genetically parallel, models to investigators and clinicians advancing studies to understand mechanisms of human genetic pathogenesis and to evaluate new therapeutic strategies. Several t To l g (2)