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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。我们正在开发非人类灵长类动物模型系统，该系统将遗传变异纳入复杂的多基因疾病，主要集中在神经系统的痛苦。我们确定自然发生的遗传变异，在恒河猴的功能模仿人类orthopathy基因的变化。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。我们正在确定遗传和表型模仿特定人群的恒河猴队列，使我们能够阐明影响疾病相关表型的遗传相互作用，并开发一个临床前平台，用于测试直接适用于人类个性化医疗的药物基因组学药物。酒精中毒是一种药物基因组学疾病，其中多个基因各自做出适度的贡献，详细了解多基因对酒精中毒的贡献可以为开发基于药物基因组学的酒精相关问题治疗策略提供基础。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。