ALCOHOL ABUSE PHARMACOGENOMICS: BUILDING NATURALISTIC RHESUS MONKEY MODELS

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。 酒精中毒是一种药物基因组疾病，在这种疾病中，多个基因各自起到一定的作用，但 相互作用以提供相对保护或相对脆弱，使其免受酒精使用的有害后果的影响。对酒精中毒的多基因作用的详细了解可以为开发基于药物基因组学的酒精相关问题的治疗策略提供基础。这项拨款申请的重点是开发自然发生的、或自然主义的恒河猴模型，研究酒精中毒背后的人类神经遗传变异。遗传方差的自然主义建模的概念源于我们在恒河猴身上发现的新的功能多态，尽管这些多态包含与人类不同的等位基因，但与神经精神疾病和物质滥用障碍相关的同源人类基因的多态具有共同的功能和表型关联。因此，我们预测，恒河猴拥有一系列与人类酒精中毒相关的功能平行的等位基因变异，可以用来阐明影响疾病变异的遗传交互作用，并可以作为临床前平台，开发个性化的、基于药物基因组学的治疗干预措施。在这方面，对与酒精中毒有关的人类神经遗传变异在恒河猴身上进行自然主义建模，将代表第一个多基因障碍脆弱性的非人类灵长类模型。我们的目标是：1)识别新的恒河猴等位基因变异体；2)在体外对已识别的多态与人类变异体进行比较；以及3)建立已识别的功能等位基因的基因分型方法，并在NEPRC的表型特征恒河猴中产生关于基因/表型关系的领先数据。我们的长期目标是选择那些拥有重叠但不同的紊乱相关等位基因集群的恒河猴群体，这些等位基因实际上模仿了与酒精中毒相关的表型、行为和特征背后的人类多基因变异。通过多个共同的基因/表型成分的积累，可以实现对恒河猴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.