Alcohol abuse pharmacogenomics: building naturalistic rhesus monkey models

描述（由申请人提供）：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，但相互作用以提供相对保护或相对脆弱性，免受酒精使用的有害后果。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的治疗策略提供基础。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。遗传变异的自然建模的概念由我们在恒河猴中的新的功能多态性的发现证实，所述新的功能多态性虽然由与人类中出现的不同的等位基因组成，但是与涉及神经精神和物质滥用障碍的正常人类基因中的多态性共享共同的功能和表型关联（米勒et al， 2001年B; 2002年; 2004年; 2005年）。因此，我们预测，恒河猴，其中包含一系列功能平行的等位基因变异，那些涉及人类酒精中毒，可用于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。在这方面，自然建模的人类神经遗传变异与酗酒的猕猴将代表第一个非人类灵长类动物模型的多基因疾病的脆弱性。我们的目标是：1）鉴定OPRM 1、rhSHTTLPR、rhMAOA-LPR、TPH 2和NACP的新的恒河猴等位基因变体2）与人变体相比，在体外功能上评估OPRM 1、rhSHTTLPR、rhMAOA-LPR、TPH 2和NACPREP 1中鉴定的多态性;和3）开发用于鉴定的功能等位基因的基因分型测定，基因型NEPRC恒河猴，并产生在NEPRC的表型特征恒河猴的基因型/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。

DESCRIPTION (provided by applicant): 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 (Miller et al, 2001 b; 2002; 2004; 2005). Accordingly, we predict that rhesus monkeys which harbor an array of unctionally 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 rheus monkeys would represent the first nonhuman primate model of a polygenetic disorder vulnerability. Our Aims are: 1) to identify novel rhesus monkey allelic variants of OPRM1, rhSHTTLPR, rhMAOA-LPR, TPH2 and NACP (alpha-synuclein); 2) to functionally assess identified polymorphisms in OPRM1, rhSHTTLPR, rhMAOA-LPR, TPH2, and NACPREP1 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 characterised 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.