Circular RNA regulators of common drug-eliminating genes

儿童意味着具有高度动态的生理和药理学的人群更容易患上 毒品中毒。生物转化基因，通常被称为药物代谢酶和 转运蛋白，具有药理学和毒理学意义。我们已经展示了一个健壮的出生后 所有被测试的生物转化基因在肝脏中的表达激增。与之形成鲜明对比的是，这些基因并没有 在另一个主要的生物转化器官十二指肠中显示出这样的激增。有趣的是，CYP3A4的mRNA 十二指肠细胞色素P450随增龄而减少，而细胞色素P3A4蛋白随增龄而增加。环状RNA (CircRNAs)是一种新兴的调节因子，可以通过发挥microRNA的作用来增加蛋白质的产量 海绵。正如初步研究中所描述的，我们已经显示了CES1的CircRNAs的存在 (羧酸酯酶-1)、CES2、CYP3A4和PXR(孕烷x受体，生物转化的主要调节因子 基因)。它们在肝脏和十二指肠的表达模式不同，年龄也不同。中环 该项目的假设是CircRNAs调节生物转化和相关基因的表达。 基因的年龄和器官依赖的方式。其具体目标是：(1)表征序列和 CircRNAs对生物转化基因的功能，以及(2)指定CircRNAs对生物转化基因的分子作用 监管活动。要指定CircRNAs的功能，检测到的CircRNAs的真实性为 序列确认后，将确定它们的器官/年龄特异性表达；以及它们的调节活性 对它们的父母和相关基因将进行详细说明。以确定调控基因的分子作用 活性，CircRNA将被测试改变的转录速率，信使核糖核酸的衰退，翻译效率和 目的基因的蛋白质稳定性。CircRNA-miRNA-mRNA网络，已知支持海绵 机制，将为不同的器官构建生物信息。科学的前提是强有力的 原创的。这种独创性源于CircRNAs作为生物转化基因的关键调节因子的新颖性 以及他们的调节活动对年龄和器官的依赖。CircRNA已经越来越多地 然而，它们的存在和功能对 生物转化基因在很大程度上仍然未知。这些研究将填补关于如何 CircRNAs参与调节生物转化基因，这是药物有效性和安全性的关键决定因素。 显然，收集到的信息将为一个更大的项目奠定坚实的基础。

Children signify a population with highly dynamic physiology and pharmacology at increased vulnerability to drug toxicities. Biotransformation genes, commonly referred to as drug metabolizing enzymes and transporters, have both pharmacological and toxicological significance. We have shown a robust postnatal surge in hepatic expression of all biotransformation genes tested. In striking contrast, these very genes did not show such surge in the duodenum, another major biotransformation organ. Interestingly, CYP3A4 mRNA (cytochrome P450) decreased with age but CYP3A4 protein increased in the duodenum. Circular RNAs (circRNAs) are emerging regulators and implicated to increase protein production by functioning as microRNA sponges. As described in the Preliminary Study, we have shown the presence of circRNAs for CES1 (carboxylesterase-1), CES2, CYP3A4, and PXR (pregnane x receptor, a master regulator of biotransformation genes). Their expression patterns varied between the liver and duodenum as well as age. The central hypothesis of the proposed project is that circRNAs regulate the expression of biotransformation and related genes in an age and organ-dependent manner. The Specific Aims are: (1) to characterize sequences and functionality of circRNAs for biotransformation genes, and (2) to specify molecular actions of the circRNAs for regulatory activities. To specify the functionality of circRNAs, the authenticity of detected circRNAs will be sequence-confirmed, their organ/age-specific expression will be determined; and their regulatory activities toward their parent and related genes will be specified. To ascertain the molecular action for the regulatory activity, a circRNA will be tested for altered transcription rate, decay of mRNA, translational efficiency and protein stability of a target gene. The circRNA-miRNA-mRNA network, known to support the sponging mechanism, will be constructed bioinformatically for different organs. The scientific premise is strong and original. The originality stems from the novelty of circRNAs as critical regulators of biotransformation genes and the dependence of their regulatory activity on age and an organ. circRNAs have been increasingly recognized to exert critical pathophysiological functions, however, their presence and functionality for biotransformation genes remain largely unknown. These studies will have filled knowledge gaps on how circRNAs participate in regulating biotransformation genes, critical determinants in drug efficacy and safety. Clearly, information collected will serve a strong foundation for a bigger project.