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: 8172837
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 1.81万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172837
• 关键词: Biological Models; Cataloging; Catalogs; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Funding; Future; Gene Targeting; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Human; In Vitro; Individual; Institution; Macaca mulatta; Measurable; Medicine; Modeling; Nervous system structure; Neurosciences; Orthologous Gene; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physiological; Population; Research; Research Personnel; Resources; Source; Testing; United States National Institutes of Health; Variant; cohort; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 个性化医疗可以为患者提供针对特定遗传特征的药物。然而，目前的药物基因组学检测受到缺乏准确代表潜在个体遗传变异的模型系统的限制。神经科学部正在开发非人类灵长类动物模型系统，该系统包含复杂的多基因疾病的遗传变异，主要集中在神经系统的痛苦上。这项研究确定了恒河猴中自然发生的遗传变异，这些变异在功能上模仿了人类正向基因的变异。这提供了一种独特的情况，即不仅潜在的基因靶点与人类高度相似，而且致病机制也相似。我们的研究重点是识别，编目和评估恒河猴遗传变异的功能，这些遗传变异具有直接可观察和可测量的表型和生理特征，与那些潜在的人类疾病相似。首要目标是在非人灵长类动物模型中自然建模人类基因型/表型关系和药物基因组学反应方差。我们的从头多态性发现平台和正在进行的体外功能评估策略协同作用，以创建恒河猴队列，这些恒河猴队列在遗传和表型上模仿特定人群，这些人群对特定神经精神和药物基因组学疾病的易感性增加。这些队列用于阐明影响疾病相关表型的遗传相互作用，并作为临床前平台，用于开发直接适用于人类个性化医疗的特定药物基因组学药物。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和特异性地模拟多基因疾病，从而开发未来的个性化药物。