ALCOHOL ABUSE PHARMACOGENOMICS: BUILDING NATURALISTIC RHESUS MONKEY MODELS

酒精滥用药物基因组学：建立自然恒河猴模型

• 批准号: 8357966
• 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/8357966
• 关键词: Alcohol abuse; Alcoholism; Biological Models; Cataloging; Catalogs; Complex; Development; Disease; Funding; Future; Gene Targeting; Genes; Genetic; Genetic Variation; Genotype; Goals; Grant; Human; Individual; Macaca mulatta; Measurable; Medicine; Modeling; National Center for Research Resources; Nervous system structure; 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; alcohol related problem; base; cohort; cost; genetic profiling; genetic variant; human disease; nonhuman primate; pre-clinical; response; trait; treatment strategy

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. We are developing non-human primate model systems that incorporate the genetic variation underlying complex, polygenic disease focusing primarily on afflictions of the nervous system. We identify 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. We are identifying rhesus macaque cohorts that genetically and phenotypically emulate particular human populations, allowing us to elucidate the genetic interactions influencing disorder-related phenotypes and develop a preclinical platform for testing pharmacogenomic-informed drugs directly applicable to human personalized medicine. Alcoholism is a pharmacogenomic disease in which multiple genes each make modest contribution, and a detailed understanding of the polygenetic contributions to alcoholism can provide the basis for developing pharmacogenomics-based treatment strategies for alcohol-related problems. 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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 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。我们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。我们在恒河猴身上发现了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。我们正在识别在基因和表型上模仿特定人类群体的恒河猴队列，使我们能够阐明影响疾病相关表型的遗传交互作用，并开发一个临床前平台，用于测试直接适用于人类个性化药物的药物基因组信息。酒精中毒是一种多基因参与的药物基因组病，详细了解多基因对酒精中毒的作用，可为制定基于药物基因组学的酒精相关问题治疗策略提供依据。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。