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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 细胞色素P450（CYP 2D 6，CYP 2C 9，CYP 2C 19）超家族中的药物代谢酶基因存在遗传多态性，这可能有助于解释多种药物代谢率的显著差异。这种遗传多态性在CYP 3A 4中尚未发现，CYP 3A 4负责代谢超过50%的处方药。有一个关键的需要，以阐明控制可变基因表达和酶功能的这一重要蛋白质的遗传多态性。CYP 3A 4的基因表达在转录水平上受核受体介导的网络调控，其中关键的转录调控因子是孕烷X受体（PXR）、组成型雄烷受体（CAR）和维甲酸X受体（RXR）的核受体。CYP 3A 4的酶功能需要辅酶P450氧化还原酶（POR）为氧化反应提供电子。本申请的目的是确定PXR、CAR、RXR α和POR基因中的遗传多态性对肝脏中不同CYP 3A 4介导的药物代谢率表现的贡献。本研究拟系统地研究细胞核受体介导网络中基因的遗传多态性对CYP 3A 4基因表达和酶活性的功能影响。确定这些基因的遗传多态性并将这些基因多态性与CYP 3A 4酶活性相关联，将为进一步评价40%的处方药经该酶代谢的药物代谢的个体间差异提供强有力的科学依据。