ALCOHOL ABUSE PHARMACOGENOMICS: BUILDING NATURALISTIC RHESUS MONKEY MODELS

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。 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贡献，但 相互作用，使相对保护或相对脆弱的有害后果的酒精使用。详细了解多基因对酗酒的影响可以为制定基于药物基因组学的酒精相关问题治疗策略提供基础。这项拨款申请的重点是发展自然发生的，或自然主义的恒河猴模型的人类神经遗传变异的基础酗酒。我们发现恒河猴的新功能多态性，虽然由不同的等位基因比人类中发生的，但共享共同的功能和表型关联的多态性在orthopathic人类基因中涉及神经精神和物质滥用障碍的概念，证明了自然建模的遗传变异的概念。因此，我们预测，恒河猴，其中含有一系列功能上平行的等位基因变异的人酒精中毒可能会被用来澄清影响疾病的变异的遗传相互作用，并可以作为一个临床前平台，为发展个性化的，基于药物基因组学的治疗干预措施。在这方面，恒河猴中与酒精中毒相关的人类神经遗传变异的自然建模将代表多基因疾病脆弱性的第一个非人类灵长类动物模型。我们的目标是：1）鉴定新的恒河猴等位基因变体; 2）与人类变体相比，在体外功能上评估鉴定的多态性; 3）为鉴定的功能等位基因开发基因分型测定，对NEPRC恒河猴进行基因分型，并在NEPRC的表型特征恒河猴中生成基因型/表型关系的领先数据。我们的长期目标是选择具有重叠但不同的疾病相关等位基因星座的恒河猴群体，这些等位基因实际上模拟了与酗酒相关的表型、行为和特征的人类多基因变异。通过多个共享的基因型/表型组分的积累，可以实现恒河猴中人类神经遗传变异的自然建模。

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. Alcoholism is a pharmacogenomic disease in which multiple genes each make modest contribution, but interact to render relative protection or relative vulnerability from deleterious consequences of alcohol use. A detailed understanding of the polygenetic contributions to alcoholism can provide the basis for developing pharmacogenomics-based treatment strategies for alcohol-related problems. This grant application focuses on the development of naturally occurring, or naturalistic rhesus monkey models of the human neurogenetic variance underlying alcoholism. The concept of naturalistic modeling of genetic variances is borne out of our findings of novel functional polymorphisms in rhesus monkeys that, although consisting of different alleles than occur in humans, nevertheless share common function and phenotypic association with polymorphisms in orthologous human genes implicated in neuropsychiatric and substance abuse disorders. Accordingly, we predict that rhesus monkeys which harbor an array of functionally parallel allelic variants to those implicated in human alcoholism could be utilized to clarify the genetic interactions influencing disorder variance, and could serve as a preclinical platform for the development of individualized, pharmacogenomics-based treatment interventions. In this regard, naturalistic modeling of the human neurogenetic variance associated with alcoholism in rhesus monkeys would represent the first nonhuman primate model of a polygenetic disorder vulnerability. Our Aims are: 1) to identify novel rhesus monkey allelic variants; 2) to functionally assess identified polymorphisms in vitro in comparison to human variants; and 3) to develop genotyping assays for identified functional alleles, genotype NEPRC rhesus monkeys and generate lead data on genotype/phenotype relationships in phenotypically characterized rhesus monkeys at NEPRC. Our long-term ambition is to select cohorts of rhesus monkeys that harbor overlapping yet distinct constellations of disorder-related alleles that mimic in effect human polygenetic variance underlying the phenotypes, behaviors and traits associated with alcoholism. Through the accumulation of multiple shared genotype/phenotype components, naturalistic modeling of human neurogenetic variance in rhesus monkeys can be achieved.