Regulation of drug transport proteins and drug metabolizing enzymes by nuclear receptors

核受体对药物转运蛋白和药物代谢酶的调节

• 批准号: 386569-2010
• 负责人: Urquhart, Bradley
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=505958
• 关键词: Regulation; drug; transport; proteins; metabolizing

In the traditional view drug molecules were thought to enter cells by simply passing through the cell membrane to access intracellular drug targets. Advances in molecular biology have clearly established that membrane proteins called drug transporters facilitate the uptake of drugs into cells as well as the extrusion of drugs out of cells. Together these uptake and efflux drug transporters form a molecular gateway to the entrance and exit of drug molecules from the cell. These drug transporters are now realized as well established determinants of the intracellular concentration of drugs and are therefore important determinants of drug response and efficacy. It has been well established that the amount and activity of drug transporter protein at the cell surface is under tight control by intracellular factors known as nuclear receptors. Despite many recent advances in our understanding of nuclear receptor biology, the processes that mediate the strict control over the amount of drug transporter protein at the cell surface remain poorly understood. We are studying the processes that control the amount and activity of drug transporter protein in the cell. Our studies will involve the evaluation of epigenetic changes to nuclear receptors and the resultant effect on drug transport genes and proteins. Epigenetics is a relatively new area of research that focuses on the study of changes in gene expression that are not due to changes in the sequence of DNA. Many epigenetic changes are believed to be mediated by the environment. In addition to evaluating the effect of changes to the amount of drug transporter genes and proteins at the cell surface we will also determine the effect on function by using well established drug transport assays. Determining how epigenetics intersects with nuclear receptors to regulate the amount and activity of drug transport proteins on cells will allow us to better understand how drugs reach their molecular targets and will aid in better guidance of drug design and predictability of response.

在传统的观点中，药物分子被认为是通过简单地穿过细胞膜进入细胞，从而进入细胞内的药物靶点。分子生物学的进展已经清楚地证明，称为药物转运体的膜蛋白有助于药物进入细胞内以及药物从细胞外排出。这些摄取和外排药物转运体共同形成了药物分子进入和离开细胞的分子门户。这些药物转运体现在被认为是药物细胞内浓度的既定决定因素，因此是药物反应和疗效的重要决定因素。已经证实，细胞表面药物转运蛋白的数量和活性受到被称为核受体的细胞内因素的严格控制。尽管我们对核受体生物学的理解最近取得了许多进展，但对细胞表面药物转运蛋白的严格控制过程仍然知之甚少。我们正在研究控制细胞中药物转运蛋白的数量和活性的过程。我们的研究将涉及评估核受体的表观遗传学变化以及由此对药物转运基因和蛋白质的影响。表观遗传学是一个相对较新的研究领域，其重点是研究基因表达的变化，而不是由于DNA序列的变化。许多表观遗传变化被认为是由环境介导的。除了评估细胞表面药物转运体基因和蛋白质的数量变化的影响外，我们还将使用成熟的药物转运体分析方法来确定对功能的影响。确定表观遗传学如何与核受体相交来调节细胞上药物转运蛋白的数量和活性，将使我们更好地了解药物是如何达到其分子靶点的，并将有助于更好地指导药物设计和反应的可预测性。