This proposal represents a response to Program Announcement PA-03-127, a Program intended to support """"""""Integrative and Collaborative Approaches to Research"""""""". The current application is specifically designed to """"""""integrate"""""""" Metabolomics and Pharmacogenomics to achieve a deeper understanding of the drug-response phenotype and to accelerate the establishment of genotype-phenotype correlations for drug response. Metabolomics is the study of metabolism at the """"""""global"""""""" level and involves studies of the """"""""metabolome"""""""", the entire repertoire of small molecules present in cells and/or tissues. The identities, concentrations and fluxes of these compounds represent the final product of interactions among gene sequence, gene expression, protein expression andthe cellular environment, an """"""""environment"""""""" that - in the clinical setting - includes drug exposure. Metabolomics has been identified as an important area for development under the NIH Roadmap Initiative. Pharmacogenomics is the study of the role of inheritance in individual variation in the drug response phenotype - with serious adverse drug reactions at one end of that phenotypic spectrum and lack of the desired therapeutic effect at the other. We believe that the inclusion of Metabolomic data as an additional, and highly informative """"""""intermediate phenotype"""""""" might significantly enhance our ability to understand and predict individual variation in response to therapeutic agents. We propose to test that hypothesis by adding Metabolomic analyses to ongoing Pharmacogenomic studies already funded by the NIH. Collaborating Metabolomics-Pharmacogenomics research teams will test the hypothesis that the application of Metabolomics might identify """"""""signatures"""""""" uniquely related to the drug response phenotype, using representatives of two important drug classes, an HMG CoA reductase inhibitor (simvastatin) and a specific serotonin reuptake inhibitor (escitalopram). The proposed effort to join Metabolomics and Pharmacogenomics represents an ideal example of """"""""Integrative and Collaborative Approaches to Research"""""""".
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