RHESUS MONKEY MODELS OF HUMAN NEUROPSYCHIATRIC GENETIC VARIANCE

Harvard Medical School, Boston MA

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Abstract

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. 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. The Division of Neurochemistry is developing non-human primate model systems that incorporate the genetic variation underlying complex, polygenic disease focusing primarily on afflictions of the nervous system. This research identifies 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. Our de novo polymorphism discovery platform and ongoing in vitro functional assessment strategies synergize to create rhesus macaque cohorts that genetically and phenotypically emulate particular human populations with increased vulnerability to specific neuropsychiatric and pharmacogenomic disorders. These cohorts serve to elucidate the genetic interactions influencing disorder-related phenotypes and as a preclinical platform for development of specific pharmacogenomic-informed drugs directly applicable to human personalized medicine. 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.