RESVERATROL INDUCTION OF GENE EXPRESSION VIA ACTIVATION OF CAR AND NRF2

白藜芦醇通过激活 CAR 和 NRF2 诱导基因表达

• 批准号: 7725156
• 负责人: Angela L Slitt
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725156
• 关键词: Acetaminophen; Affect; Antioxidants; Atherosclerosis; Biological Assay; Cells; Chemicals; Communities; Computer Retrieval of Information on Scientific Projects Database; Consumption; Data; Disease; Enzymes; Funding; Gene Expression; Gene Expression Regulation; Genes; Grant; Hepatocyte; Human; Institution; Liver; Luciferases; Malignant Neoplasms; Medical; Metabolism; Mus; Nuclear; Nuclear Receptors; Pharmaceutical Preparations; Phase; Property; Public Health; Rattus; Reporter; Research; Research Personnel; Resources; Response Elements; Resveratrol; Rodent Model; Source; Toxic effect; Transfection; Transgenic Mice; United States; United States National Institutes of Health; constitutive androstane receptor; fighting; in vivo; mRNA Expression; red wine; trans-stilbene oxide; transcription factor

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. Red wine consumption in the United States has increased because the popular media and medical community have touted its antioxidant properties and potential to fight disease such as atherosclerosis and cancer. Thus, understanding the protective properties of resveratrol and determining appropriate rodent models to study them is important for public health. In cells and rat liver, resveratrol treatment increases the expression of several genes regulated by the Antioxidant Response Element (ARE), which are important for Phase-I and -II metabolism. A mechanism by which resveratrol may exert its protective properties is through induction of gene expression via activation AREs. Preliminary data demonstrates that trans-stilbene oxide (TSO), a chemical structurally similar to resveratrol, increases the mRNA expression of some genes encoding Phase-I and -II drug metabolizing enzymes (DMEs), and drug transporters. TSO activates two transcription factors that regulate expression of DMEs and transporters, namely the Constitutive Androstane Receptor (CAR) and Nuclear Factor-E2-Related Factor (NRF2). We hypothesize that resveratrol induces the expression of genes for Phase-I, and -II DMEs, as well as transporters, in hepatocytes through activation of CAR and NRF2. Specific aim 1 will determine whether resveratrol treatment increases Phase-I, -II DME expression and transporter expression in human hepatocytes and mouse liver. Specific aim 2 will determine whether resveratrol activates CAR and Nrf2 using transient transfection and in vivo luciferase assays with Nuclear Receptor-1 and ARE/EpRE-luciferase reporter constructs, as well as transgenic mice possessing an ARE-luciferase reporter. Specific aim 3 will determine whether RES pretreatment affects acetaminophen metabolism, disposition, and toxicity. Together, these studies will determine whether resveratrol exposure alters expression of human and genes for DMEs and transporters, and whether a species similarity in regulation of these genes exists. The studies will also determine whether resveratrol exerts its protective properties through activation of nuclear receptors, specifically CAR and Nrf2.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 美国的红酒消费量有所增加，因为大众媒体和医学界都吹捧其抗氧化特性以及对抗动脉粥样硬化和癌症等疾病的潜力。 因此，了解白藜芦醇的保护特性并确定合适的啮齿动物模型来研究它们对于公共卫生非常重要。 在细胞和大鼠肝脏中，白藜芦醇治疗可增加受抗氧化反应元件 (ARE) 调节的多种基因的表达，这些基因对于 I 期和 II 期代谢非常重要。 白藜芦醇发挥其保护特性的机制是通过激活 ARE 诱导基因表达。 初步数据表明，反式二苯乙烯氧化物 (TSO) 是一种结构类似于白藜芦醇的化学物质，可增加编码 I 期和 II 期药物代谢酶 (DME) 和药物转运蛋白的一些基因的 mRNA 表达。 TSO 激活两个调节 DME 和转运蛋白表达的转录因子，即组成型雄甾烷受体 (CAR) 和核因子 E2 相关因子 (NRF2)。 我们假设白藜芦醇通过激活 CAR 和 NRF2 来诱导肝细胞中 I 期和 II 期 DME 以及转运蛋白的基因表达。 具体目标 1 将确定白藜芦醇治疗是否会增加人肝细胞和小鼠肝脏中 I、II 期 DME 表达和转运蛋白表达。 具体目标 2 将使用核受体 1 和 ARE/EpRE 荧光素酶报告基因构建体以及具有 ARE 荧光素酶报告基因的转基因小鼠进行瞬时转染和体内荧光素酶测定，确定白藜芦醇是否激活 CAR 和 Nrf2。 具体目标 3 将确定 RES 预处理是否影响对乙酰氨基酚的代谢、处置和毒性。 这些研究将共同​​确定白藜芦醇暴露是否会改变人类以及 DME 和转运蛋白的基因表达，以及这些基因的调节是否存在物种相似性。 这些研究还将确定白藜芦醇是否通过激活核受体（特别是 CAR 和 Nrf2）发挥其保护特性。