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. The UCSF PMT Project is a multi-disciplinary research program focused on the pharmacogenetics of membrane transport proteins that play a role in drug response pathways. The project seeks to understand the genetic basis for variation in drug response for drugs which interact with membrane transport proteins. This class of proteins is of great pharmacological importance as it provides the target for many commonly used prescription drugs and is a major determinant of the absorption, distribution and elimination of many clinically used drugs. This project seeks to test the hypothesis that variations in the DNA sequence of genes encoding membrane transporters underlie inter-individual differences in response to such drugs. To accomplish this, the program is structured around six interacting cores: genomics, cellular phenotyping, clinical phenotyping, biostatistics, shared resources/collaborations, and bioinformatics. The project also facilitate studies by contributing data to the publicly available knowledge base, PharmGKB (www.pharmgkb.org/). The overall aims of the PMT project are to: a) Identify sequence variants in membrane transporter genes in the SLC and ABC superfamilies. b) Determine cellular phenotypes for transporter variants through experimental and computational methods. c) Determine the biological relevance of variants in membrane transporters to clinical drug response. d) Deposit the data in PharmGKB and develop shared resources for the pharmacogenetics research community. In this collaborative project, we are developing new methods for data collection and analysis of these experiments. This includes developing automated methods to store, analyze, summarize, and disseminate to researchers the genomic, cellular, and clinical data. We work closely with the UCSF Genomics Core Facility (GCF) developing protocols that enable them to transmit high quality sequence and multiple alignment genomic data amenable to high-throughput analysis. We also provide to the GCF quality assessment of sequence data using the phred and phrap software packages. We develop, test, and implement software tools to analyze the data and summarize the analysis results from multiple perspectives and at various granularities. The results are communicated rapidly to PMT investigators via programmatically constructed web pages in tabular and graphical forms. We work with the PMT investigators to identify additional analyses, both for ad hoc implementation and for incorporation into the high-throughput analyses. At the appropriate time, we transmit the data to the PharmGKB database at Stanford University. We also maintain a project intranet that contains information on the program activities, including data and analysis on transporters currently under study. The PMT public website, password-protected intranet, database, and data processing pipelines are hosted by the RBVI. Nearly 100 million nucleotides of sequence data have been collected for 663 exons from dozens of transporters, resulting in more than 1500 variants deposited in PharmGKB. For additional details see www.cgl.ucsf.edu/Research/pmt/
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