In this renewal application, we propose to continue and extend our multi-disciplinary research program focused on the pharmacogenetics of membrane transport proteins that play a role in drug response pathways. Our proposed studies are focused on two major superfamilies of transporters: Solute Carrier (SLC) and ATP Binding Cassette (ABC).
Our specific aims are to: (a) Identify sequence variants in 125 membrane transporter genes in 360 ethnically diverse DMA samples, (b) Determine cellular phenotypes for transporter variants, (c) Determine the biological relevance of variants in membrane transporters to clinical drug response, (d) Deposit the data in PharmGKB and develop shared resources. We will identify SNPs in coding, promoter and conserved non-coding regions. Cellular studies exploring the functional consequences of coding and promoter region variants and computationl studies to develop predictive algorithms of function will be carried out. For our genotype to phenotype clinical studies, we will assemble SOPHIE-500 (Studies of Pharmacogenetics in Ethnically diverse populations), a unique cohort of ethnically diverse healthy volunteers who have donated DMA for SNP discovery and agreed to be called back for follow-up pharmacogenetic studies. Two such studies are proposed. Our phenotype to genotype studies involve GRAD, the Genetics of Response to Anti-Depressants, a rich resource that has accrued over 1000 individuals and contains information about response and adverse drug response to anti-depressants. Our project is organized around six interacting cores (genomics, cellular phenotyping, clinical phenotyping, biostatistics, shared resources/collaborations and bioinformatics). Our studies will make significant contributions to PharmGKB, and will result in the development of numerous cell lines and plasmids as shared resources. These hypothesis generating studies will provide a framework for understanding the role of genetic variation in membrane transporters on clnical drug response. ? ?
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