RHESUS MONKEY MODELS OF HUMAN NEUROPSYCHIATRIC GENETIC VARIANCE

人类神经精神遗传变异的恒河猴模型

• 批准号: 8357930
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357930
• 关键词: Biological Models; Cataloging; Catalogs; Complex; Development; Disease; Funding; Future; Gene Targeting; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Human; In Vitro; Individual; Macaca mulatta; Measurable; Medicine; Modeling; National Center for Research Resources; Nervous system structure; Neurosciences; New England; Orthologous Gene; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physiological; Population; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Source; Testing; United States National Institutes of Health; Variant; base; cohort; cost; genetic profiling; genetic variant; human disease; neuropsychiatry; nonhuman primate; pre-clinical; response; trait

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Personalized medicine can offer patients drugs that are tailored to specific genetic profiles. Current pharmacogenomic testing, however, is limited by a lack of model systems which accurately represent the underlying individual genetic variation. The Division of Neuroscience is developing non-human primate model systems that incorporate the genetic variation underlying complex, polygenic disease focusing primarily on afflictions of the nervous system. This research identifies naturally-occurring genetic variation in rhesus monkeys that functionally mimics variation in human orthologous genes. This offers the unique situation that not only is the underlying gene target highly similar to humans but the disease-causing mechanisms are similar as well. Our research has focused on identifying, cataloging, and assessing the functionality of rhesus monkey genetic variants with directly observable and measurable phenotypic and physiological traits paralleling those underlying human disorders. The overarching goal is to naturalistically model human genotype/phenotype relationships and pharmacogenomic response variance in a non-human primate model. Our de novo polymorphism discovery platform and ongoing in vitro functional assessment strategies synergize to create rhesus macaque cohorts that genetically and phenotypically emulate particular human populations with increased vulnerability to specific neuropsychiatric and pharmacogenomic disorders. These cohorts serve to elucidate the genetic interactions influencing disorder-related phenotypes and as a preclinical platform for development of specific pharmacogenomic-informed drugs directly applicable to human personalized medicine. This research offers an unprecedented opportunity to accurately and specifically model polygenic disorders in a highly translational setting allowing for the development of the personalized drugs of the future.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 个性化药物可以为患者提供针对特定遗传特征的药物。然而，当前的药物基因组学测试受到缺乏准确代表基本遗传变异的模型系统的限制。神经科学的划分正在开发非人类灵长类动物模型系统，该系统结合了基本复合物，多基因疾病的基因变异，主要集中在神经系统的痛苦上。这项研究确定了恒河猴的自然遗传变异，这些猴子在功能上模仿了人类直系同源基因的变异。这提供了独特的情况，不仅基本基因靶标与人类高度相似，而且引起疾病的机制也相似。我们的研究重点是鉴定，分类和评估恒河猴遗传变异的功能，其直接可观察到的表型和生理特征与与基本人类疾病相关的表型和生理特征。总体目标是自然而然地模拟非人类灵长类动物模型中的人类基因型/表型关系和药物基因组反应方差。我们的从头多态性发现平台和持续的体外功能评估策略协同创建恒河猴猕猴同类群体，从遗传和表型上仿真人类人群，对特定的神经精神病学和药物基因组障碍的脆弱性增加。这些队列阐明了影响疾病相关表型的遗传相互作用，并作为开发直接适用于人类个性化医学的特定药物基因组知识的药物的临床前平台。这项研究提供了一个前所未有的机会，可以在高度转化的环境中准确，专门针对多基因疾病进行建模，从而开发未来的个性化药物。