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。 美国的红酒消费量增加了，因为受欢迎的媒体和医学界吹捧其抗氧化特性以及与动脉粥样硬化和癌症等疾病作斗争的潜力。 因此，了解白藜芦醇的保护特性并确定适当的啮齿动物模型来研究它们对于公共卫生很重要。 在细胞和大鼠肝脏中，白藜芦醇处理增加了由抗氧化剂反应元件（AS）调节的几种基因的表达，这对于I期和-II代谢很重要。 白藜芦醇可以通过激活ARES诱导基因表达的机制是通过激活ARES诱导基因表达。 初步数据表明，在结构上与白藜芦醇相似的化学化学氧化苯（TSO）增加了编码一些编码I期I和-II药物代谢酶（DME）和药物转运蛋白的一些基因的mRNA表达。 TSO激活了调节DME和转运蛋白表达的两个转录因子，即构型雄激素受体（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在肝细胞中诱导基因的表达，-II DME和转运蛋白。 特定的目标1将确定白藜芦醇处理是否会增加人肝细胞和小鼠肝脏中的I期，-II DME表达和转运蛋白的表达。 特定的目标2将使用瞬时转染和核受体1和IS/epre-酸酶酶报告构建体以及具有LEACIFERASE RECORTER的转基因小鼠的瞬时转染和体内荧光素酶测定来确定白藜芦醇是否会激活CAR和NRF2。 具体目标3将确定RES预处理是否会影响对乙酰氨基酚的代谢，性格和毒性。 这些研究将共同​​确定白藜芦醇暴露是否会改变DME和转运蛋白的人类和基因的表达，以及这些基因调节中的物种相似性是否存在。 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）施加其保护性能。