Pharmacogenetics of Phase II Drug Metabolizing Enzymes

描述（由申请人提供）：本提案代表了继续执行 马约临床药物遗传学研究网络（PGRN）研究项目“II期药物代谢酶的药物遗传学”。马约PGRN是一个综合的、多学科的、多机构的研究工作，它本身就被整合到NIH赞助的多机构PGRN中。马约PGRN基于马约数十年来对II期（结合）药物代谢酶的药物遗传学和药物基因组学研究。这些酶也催化激素如雌激素和单胺神经递质的结合。马约PGRN利用了基因型-表型研究策略，该策略首先对编码II相酶的基因进行重新测序，然后对这些基因中存在的遗传多态性的功能效应进行表征-特别强调这些多态性影响功能的机制。在下一个供资期内，将继续并扩大这一做法-继续强调向药物遗传学和药物基因组学研究界提供关于II期酶的遗传多态性、功能基因组学和机理数据-但也将这一研究扩大到包括芳香酶抑制剂阿那曲唑和选择性5-羟色胺再摄取抑制剂（SSRI）艾司西酞普兰的药物基因组学研究。这两项临床药物基因组学研究都直接基于马约PGRN药物基因组学研究的长期历史，即II相酶在雌激素结合（由芳香酶合成）和单胺神经递质结合（其功能被SSRI（如艾司西酞普兰）改变）中的作用。 马约PGRN进行的研究所获得的所有药物基因组学信息将迅速保存在NIH赞助的Pharm

DESCRIPTION (provided by applicant): This proposal represents a request for continuation of the Mayo Clinic Pharmacogenetics Research Network (PGRN) Research Program "Pharmacogenetics of Phase II Drug Metabolizing Enzymes". The Mayo PGRN is an integrated, multidisciplinary, multi-institutional research effort that is itself integrated within the overall NIH-sponsored multi-institution PGRN. The Mayo PGRN is based on a decades-long focus at Mayo on studies of the pharmacogenetics and pharmacogenomics of phase II (conjugating) drug-metabolizing enzymes. Those same enzymes also catalyze the conjugation of hormones such as estrogens and of monoamine neurotransmitters. The Mayo PGRN has utilized a genotype-to-phenotype research strategy that begins by re-sequencing genes which encode phase II enzymes, followed by characterization of the functional effects of genetic polymorphisms present in these genes -- with a special emphasis on mechanisms by which those polymorphisms influence function. That approach will be continued and expanded during the next funding period -- with a continued emphasis on providing genetic polymorphism, functional genomic and mechanistic data on phase II enzymes to the pharmacogenetic and pharmacogenomic research community - but also extending this research to include studies of the pharmacogenomics of the aromatase inhibitor anastrozole and the selective serotonin reuptake inhibitor (SSRI) escitalopram. Both of these clinical pharmacogenomic studies are based directly on the long history of Mayo PGRN pharmacogenomic studies of the role of phase II enzymes in the conjugation of estrogens, which are synthesized by aromatase, and the conjugation of monoamine neurotransmitters, whose function is altered by SSRIs such as escitalopram. All pharmacogenomic information obtained as a result of the research conducted by the Mayo PGRN will be rapidly deposited in the NIH-sponsored Pharm