Pharmacogenetics of Phase II Drug Metabolizing Enzymes

描述(由申请人提供)：本建议书代表请求继续 梅奥临床药物遗传学研究网络(PGRN)研究计划“药物代谢酶二期药物遗传学”。梅奥PGRN是一个综合的、多学科、多机构的研究成果，它本身就被整合到整个NIH赞助的多机构PGRN中。Mayo PGRN是基于Mayo数十年来专注于第二阶段(结合)药物代谢酶的药物遗传学和药物基因组学研究。这些酶还催化雌激素等激素和单胺类神经递质的结合。Mayo PGRN利用了从基因型到表型的研究策略，首先对编码II相酶的基因进行重新测序，然后描述这些基因中存在的遗传多态的功能效应，并特别强调这些多态影响功能的机制。这一方法将在下一个资助期继续和扩大--继续强调向药物遗传学和药物基因组研究界提供第二阶段酶的遗传多态、功能基因组和机械学数据--但也扩大这项研究，以包括芳香化酶抑制剂阿那曲唑和选择性5-羟色胺再摄取抑制剂(SSRI)爱司匹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Mayo PGRN的长期药物基因组学研究，即II相酶在雌激素结合中的作用(由芳香酶合成)和单胺神经递质的结合作用，单胺类神经递质的功能被诸如艾司匹兰等SSRIs改变。由Mayo PGRN进行的研究获得的所有药物基因组学信息将迅速存储在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