This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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. Our research 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 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 rheus monkeys would represent the first nonhuman primate model of a polygenetic disorder vulnerability. We are identifying novel rhesus monkey allelic variants of OPRM1, rh5HTTLPR, rhMAOA-LPR, TPH2 and NACP (alpha-synuclein), functionally assessing identified polymorphisms in comparison to human variants, and developing genotyping assays for identified functional alleles. 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.
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