IDENTIFICATION & FUNCTIONAL CHARACTERIZATION OF SNPS IN RXRA GENE

鉴别

• 批准号: 7959507
• 负责人: XIAO-BO ZHONG
• 金额: $ 19.67万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959507
• 关键词: CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; CYP3A4 gene; Coenzymes; Computer Retrieval of Information on Scientific Projects Database; Cytochrome P450; Disease; Drug Prescriptions; Electrons; Enzyme Gene; Enzymes; Evaluation; Foundations; Funding; Gene Expression; Genes; Genetic Polymorphism; Grant; Health; Individual Differences; Institution; Liver; Mediating; Metabolic; Nuclear Receptors; Oxidoreductase; Oxidoreductase Gene; Pharmaceutical Preparations; Pregnanes; Proteins; RXRA gene; Reaction; Research; Research Personnel; Resources; Retinoids; Source; United States National Institutes of Health; constitutive androstane receptor; drug metabolism; enzyme activity; oxidation; receptor

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. Genetic polymorphisms have been identified in drug-metabolizing enzyme genes of cytochrome-P450 (CYP) superfamily, such as CYP2D6, CYP2C9, and CYP2C19, which may help to explain significant differences in the metabolic rates for a variety of drugs. Such genetic polymorphisms have not been identified in CYP3A4 which is responsible for metabolizing more than 50% of prescription drugs. There is a critical need to elucidate the genetic polymorphisms that control variable gene expression and enzyme functions of this important protein. Gene expression of CYP3A4 is regulated at transcriptional level by a nuclear receptor mediated network, in which key transcriptional regulatory factors are nuclear receptors of pregnane-x-receptor (PXR), constitutive androstane receptor (CAR), and retinoid x receptor (RXR). Enzyme functions of CYP3A4 required a coenzyme, P450 oxidoreductase (POR), to provide electrons for oxidation reactions. The objective of this application is to determine the contribution of genetic polymorphisms in the PXR, CAR, RXRalpha, and POR genes to the manifestations of differential CYP3A4-mediated drug metabolic rates in liver. We propose to systematically exam functional influence of genetic polymorphisms in genes in the nuclear receptor mediated network on CYP3A4 gene expression and enzyme activity. The identification of genetic polymorphisms among these genes and to correlate these genetic polymorphisms with CYP3A4 enzyme activity, will provide a strong scientific foundation for further evaluation of inter-individual differences of drug metabolism for the 40% of prescription drugs metabolized by this enzyme.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在药物代谢化酶基因中已经鉴定出细胞色素-P450（CYP）超家族的遗传多态性，例如CYP2D6，CYP2C9和CYP2C19，这可能有助于解释各种药物代谢率的显着差异。在CYP3A4中尚未鉴定出这种遗传多态性，该遗传多态性负责代谢超过50％的处方药。迫切需要阐明控制这种重要蛋白质的可变基因表达和酶功能的遗传多态性。 CYP3A4的基因表达在转录水平下通过核受体介导的网络调节，其中关键转录调节因子是妊娠X受体（PXR）（PXR），组成型雄激素受体（CAR）和维替素X受体（RXR）的核受体。 CYP3A4的酶功能需要P450氧化还原酶（POR）的辅酶，以提供电子用于氧化反应。该应用的目的是确定PXR，CAR，RXRALPHA和POR基因对遗传多态性的贡献，对肝脏中差异CYP3A4介导的药物代谢率的表现。我们建议在核受体介导的CYP3A4基因表达和酶活性的核受体介导的网络中系统地检查遗传多态性的功能影响。这些基因之间遗传多态性的鉴定，并将这些遗传多态性与CYP3A4酶活性相关联，将为该酶代谢的40％的处方药对药物代谢之间的个体代谢差异进一步评估，这将为进一步的科学基础。