Does the Lack of MRP1 Alter Expression of Other Genes?

MRP1 的缺失是否会改变其他基因的表达？

• 批准号: 6664240
• 负责人: LISA J BAIN
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664240
• 关键词: complementary DNA; cytochrome P450; cytotoxicity; enzyme activity; etoposide; gene expression; genetic regulation; genetically modified animals; glutathione; laboratory mouse; membrane transport proteins; microarray technology; testis

DESCRIPTION (provided by applicant): The multidrug resistance-associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) protein family. Member of this family of transporters actively transport predominantly glucuronide, glutathione, and sulfate conjugated compounds out of cells, Mice lacking the MRP1 protein (termed FVB/mrpl-/- mice) have been produced. While the animals are viable and fertile, MRP1 clearly plays a role in protecting the mice from the toxicity of a variety of compounds, including anticancer drugs such as etoposide. In preliminary studies, we have shown that MRP1 also protects the testicular tubules from methoxychlor toxicity. During the course of that study, we realized that activity of several cytochrome P450 proteins was significantly lowered in control wild type mice compared to control FVB/mrpl-/- mice. Therefore, we would like to further examine the differences in gene expression in mice lacking the multidrug resistance-associated protein 1 (MRPI/ABCC1) compared to wild-type mice. The hypothesis to be tested is that the loss of this transporter, while not lethal, results in the up- and down-regulation of a variety of genes to compensate for its loss, presumably in a tissue-specific manner. Using this information, we can better understand coordinate regulation between transporters and other genes that regulate them, or genes that are in detoxification and elimination pathways. This information will ultimately be invaluable for using these mice to determine drug disposition and the potency or specificity of anticancer drugs.

描述（由申请人提供）：多药抗性相关蛋白1（MRP1/ABCC1）是ATP结合盒（ABC）蛋白质家族的成员。该转运蛋白家族的成员积极运输主要是葡萄糖醛酸，谷胱甘肽和硫酸盐共轭化合物，从细胞中脱离，缺乏MRP1蛋白（称为FVB/MRPL - / - 小鼠）的小鼠。尽管动物是可行且肥沃的，但MRP1显然在保护小鼠免受各种化合物的毒性（包括抗癌药物（例如依托泊苷））的毒性中起作用。在初步研究中，我们表明MRP1还保护睾丸小管免受甲氧基毒性的毒性。在这项研究过程中，我们意识到，与对照FVB/MRPL - / - 小鼠相比，对照野生型小鼠的几种细胞色素P450蛋白的活性显着降低。因此，我们想进一步研究与野生型小鼠相比，缺乏多药相关蛋白1（MRPI/ABCC1）的小鼠的基因表达差异。要检验的假设是，该转运蛋白的丢失虽然不是致命的，但会导致各种基因的上调和下调以补偿其损失，这可能是以组织特异性方式进行的。使用这些信息，我们可以更好地理解转运蛋白与调节它们的其他基因之间的坐标调节，或在解毒和消除途径中的基因。最终，对于使用这些小鼠来确定药物处置以及抗癌药物的效力或特异性将是无价的。