Circular RNA regulators of common drug-eliminating genes

常见药物消除基因的环状RNA调节因子

• 批准号: 10684130
• 负责人: Bingfang Yan
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684130
• 关键词: Age; Age Months; Bioinformatics; CYP3A4 gene; Carboxylesterase 1; Child; Cytochrome P450; Dependence; Disease; Drug Kinetics; Drug toxicity; Duodenum; Enzymes; Exhibits; Foundations; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Hepatic; Human; Human Genome; Knowledge; Laboratories; Life; Liver; Messenger RNA; Metabolic Biotransformation; MicroRNAs; Molecular; Organ; Parents; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Physiology; Population; Porifera; Post-Transcriptional Regulation; Production; Proteins; RNA; RNA library; Recording of previous events; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Specific qualifier value; Testing; Therapeutic; Toxicology; Transcriptional Activation; Translations; Xenobiotics; age group; carboxylesterase; circular RNA; design; drug efficacy; evidence base; experimental study; genetic testing; insight; mRNA Decay; medication safety; originality; pharmacologic; postnatal; pregnane X receptor; protein expression; stem; trend

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.

儿童意味着具有高度动态生理学和药理学的人群，更容易受到影响 药物毒性。生物转化基因，通常称为药物代谢酶和 转运蛋白，具有药理学和毒理学意义。我们展现了强大的产后能力 所有测试的生物转化基因的肝脏表达激增。与此形成鲜明对比的是，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种激增。有趣的是，CYP3A4 mRNA （细胞色素 P450）随着年龄的增长而减少，但十二指肠中的 CYP3A4 蛋白增加。环状RNA （circRNA）是新兴的调节因子，通过充当 microRNA 来增加蛋白质产量 海绵。正如初步研究中所述，我们已经证明了 CES1 的 circRNA 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）。它们的表达模式在肝脏和十二指肠以及年龄之间存在差异。中央 该项目的假设是 circRNA 调节生物转化和相关的表达 基因以年龄和器官依赖性方式。具体目标是： (1) 表征序列和 circRNA 对于生物转化基因的功能，以及 (2) 指定 circRNA 的分子作用 监管活动。为了指定 circRNA 的功能，检测到的 circRNA 的真实性将是 序列确认后，将确定其器官/年龄特异性表达；及其监管活动 将指定其父母和相关基因。确定监管的分子作用 活性，将测试 circRNA 的转录率改变、mRNA 衰减、翻译效率和 靶基因的蛋白质稳定性。 circRNA-miRNA-mRNA 网络，已知支持海绵作用 机制，将为不同器官构建生物信息学。科学前提是强有力的 原来的。原创性源于 circRNA 作为生物转化基因关键调节因子的新颖性 以及它们的调节活动对年龄和器官的依赖性。 circRNA 已越来越多地 公认发挥关键的病理生理功能，然而，它们的存在和功能 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 circRNA 参与调节生物转化基因，是药物功效和安全性的关键决定因素。 显然，收集到的信息将为更大的项目奠定坚实的基础。

项目成果

Covalent CES2 Inhibitors Protect against Reduced Formation of Intestinal Organoids by the Anticancer Drug Irinotecan.

共价 CES2 抑制剂可防止抗癌药物伊立替康减少肠道类器官的形成。

• DOI: 10.2174/1389200224666221212143904
• 发表时间: 2022
• 期刊: Current drug metabolism
• 影响因子: 2.3
• 作者: Eades,William;Liu,William;Shen,Yue;Shi,Zhanquan;Yan,Bingfang
• 通讯作者: Yan,Bingfang

Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus.

• DOI: 10.1016/j.bcp.2022.115224
• 发表时间: 2022-10
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Liu, William;Yu, Sarah;Yan, Bingfang
• 通讯作者: Yan, Bingfang

Differentiated embryonic chondrocyte expressed gene-1 is a central signaling component in the development of collagen-induced rheumatoid arthritis.

分化的胚胎软骨细胞表达的gene-1是胶原诱导的类风湿性关节炎发展中的核心信号成分。

• DOI: 10.1016/j.jbc.2023.102982
• 发表时间: 2023-03
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Wu, Yichen;Wang, Haobin;Huo, Ying;Yan, Bingfang;Honda, Hiroaki;Liu, Wei;Yang, Jian
• 通讯作者: Yang, Jian