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Epigenetic and Genetic Dissection of Drug Response

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Elucidating the organization of genetic networks and establishing how they contribute to cellular and organismal phenotypes remain to be a grand challenge in our genomic era. Drug response and gene expression are complex phenotypes that are controlled by various genetic and non-genetic factors. Developing genome-based approaches to prediction of drug response could potentially be used in individualized medicine to maximize benefits and minimize harms. A more comprehensive and better characterization of the genetic, epigenetic factors determining complex phenotypes such as drug response, therefore, may significantly benefit the heath of our citizens and provide development opportunities for our biomedical industry. Taking advantage of the rich genetic variation data (e.g., genotypes of ~3.1 million single nucleotide polymorphisms, SNPs) on the International HapMap Project samples, a panel of human lymphoblastoid cell lines (LCLs) derived from apparently healthy individuals, the Dolan (Co-PI of this proposal) Laboratory has pioneered using the LCL model system in pharmacogenomic discovery by integrating genetic and phenotypic data on these samples. Since DNA methylation at the CpG sites of gene promoter regions is a crucial mechanism of gene expression regulation, expanding the current whole genome genetic (e.g., SNP genotypes) and phenotypic data (e.g., mRNA and microRNA expression) on these samples to include DNA methylation may provide novel and critical insights into the underlying mechanism of individual drug response and expression regulation, and reflect a significantly new direction for pharmacogenomic and gene expression studies. We therefore propose to use the NimbleGen 2.1M Deluxe Promoter Array and the MeDIP (methylated DNA immunoprecipitation) assay to profile the natural variation in DNA methylation status at all known promoter regions in 60 unrelated cell lines from the HapMap CEU (derived from Caucasian residents from Utah, USA) samples of Northern and Western European ancestry. The relationships across SNP genotypes, promoter DNA methylation status, gene expression and drug response will be investigated systematically to evaluate the contribution of epigenetics (specifically, DNA methylation) and genetics (specifically, SNPs) to the cytotoxicities of 12 anticancer drugs. Since gene expression is of broad interest to the entire biomedical research community, the primary individual-level DNA methylation data and the methylation-associated signatures for both gene expression and drug response will be put in public domain as a web-based database for easy use and re-analysis. Upon completion, this exploratory project will significantly enhance scientific knowledge in the broad fields of genomics and pharmacogenomics. Finally, the multi-disciplinary nature of our investigative team and the complementary expertise of PIs enhance our ability to conduct the proposed project successfully.
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