RHESUS MONKEY MODELS OF HUMAN NEUROPSYCHIATRIC GENETIC VARIANCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 个性化药物可以为患者提供针对特定基因特征量身定做的药物。然而，目前的药物基因组测试受到缺乏准确代表潜在个体遗传变异的模型系统的限制。神经化学部正在开发非人类灵长类动物模型系统，其中包括主要关注神经系统疾病的复杂多基因疾病背后的遗传变异。这项研究确定了恒河猴中自然发生的遗传变异，这种变异在功能上模仿了人类同源基因的变异。这提供了一种独特的情况，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，这些变异具有与人类潜在疾病相似的直接可观察和可测量的表型和生理特征。总体目标是在非人类灵长类动物模型中自然地模拟人类基因/表型关系和药物基因组反应差异。我们的从头开始的多态发现平台和正在进行的体外功能评估策略相结合，创建了恒河猴队列，这些队列在基因和表型上模仿了易患特定神经精神和药物基因组疾病的特定人群。这些队列用于阐明影响疾病相关表型的遗传相互作用，并作为开发直接适用于人类个性化药物的特定药物基因组信息的临床前平台。这项研究提供了一个前所未有的机会，可以在高度翻译的环境中准确和具体地模拟多基因疾病，从而允许开发未来的个性化药物。

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 Neurochemistry 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.